Cephalosporin derivatives

ABSTRACT

The present invention relates to novel cephalosporin derivatives, processes for preparing thereof, compositions for preventing and/or treating infectious diseases which comprise the novel cephalosporin derivatives as active components, and the intermediate compounds in the synthesis of cephalosporin derivatives and processes for producing thereof. 
     The present invention is based on the selection of groups containing a condensed heterocyclic ring, particularly a triazolopyrimidine ring or a thiadiazolopyrimidine ring, as substituents at the 3-position of the cephem skeleton, and of groups containing a catechol moiety, particularly a catechol carboxymethyloxyimino moiety or a catechol carboxyimino moiety, as substituents at the 7-position of the cephem skeleton. 
     The compounds of the present invention containing the aforementioned substituents have a strong antibacterial activity against Gram-negative bacteria and also against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. These compounds are extremely useful for the treatment of infectious diseases.

This is a Division of application Ser. No. 838,309 filed March 10, 1986,now U.S. Pat. No. 4,840,949.

BACKGROUND OF THE INVENTION

The present invention relates to novel cephalosporin derivatives,processes for producing cephalosporin derivatives, and compositionscontaining cephalosporin derivatives for treating and/or preventinginfectious diseases.

Developments of cephalosporin derivatives have been remarkable. Somecephalosporin derivatives have been developed which have excellentantibacterial activity against Gram-negative bacteria. However, theantibacterial activity of these cephalosporin derivatives againstGram-positive bacteria is rather poor. Several cephalosporin antibioticshave been used for the treatment of Gram-positive bacteria infectionsand the increase of Gram-positive bacteria resistant to cephalosporinantibiotics, for example, methicillin-resistant Staphylococcus aureus(MRSA), has become widely known year by year.

From the foregoing background, it has been desired to developcephalosporin derivatives having a strong antibacterial activity againstGram-positive bacteria while retaining a sufficient antibacterialactivity against Gram-negative bacteria.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel cephalosporinderivatives and salts, hydrates and salts of hydrates thereof.

Another object of the present invention is to provide processes forproducing novel cephalosporin derivatives.

A further object of the present invention is to provide compositions forpreventing and/or treating infectious disease which comprise novelcephalosporin derivatives as active compounds.

A further object of the present invention is to provide intermediatecompounds in the synthesis of cephalosporin derivatives and processesfor producing such intermediate compounds.

The present invention is based on the selection of groups containing acondensed heterocyclic ring, particularly a triazolopyrimidine ring or athiadiazolopyreimidine ring, as substituents at the 3-position of thecephem skeleton, and of groups containing a catechol moiety,particularly a catechol carboxymethyloxyimino moiety or a catecholcarboxyimino moiety, as substituents at the 7-position of the cephemskeleton.

The compounds of the present invention containing these substituentshave a wide antibacterial spectrum against Gram-negative bacteria andGram-positive bacteria including methicillin-resistant Staphylococcusaureus. These compounds are extremely useful for the treatment ofinfectious diseases.

DETAILED DESCRIPTION OF THE INVENTION

As a result of extensive investigations concerning development ofcephalosporin derivatives having a satisfactory antibacterial activityagainst Gram-negative bacteria and also having strong antibacterialactivity against Gram positive bacteria, the present inventors havefound that cephalosporin derivatives represented by the general formula(I) satisfy these requirements and, have accomplished the presentinvention.

The present invention is based on the selection of groups containing acondensed heterocyclic ring, particularly a triazolopyrimidine ring or athiadiazolopyrimidine ring, as substituents at the 3-position of thecephem skeleton, and of groups containing a cathechol moiety,particularly a catechol carboxymethyloxyimino moiety or a catecholcarboxyimino moiety, as substituents at the 7-position of the cephemskeleton.

The present invention is directed to cephalosporin derivativesrepresented by the general formula (I): ##STR1## and salts, hydrates andsalts of hydrates thereof; wherein R¹ represents a hydrogen atom or anamino-protecting group, R² and R³ are the same or different andrepresent hydrogen atoms, methyl groups, carboxyl groups, protectedcarboxyl groups, or together an oxygen atom, R⁴ and R⁵ representhydrogen atoms or together an oxygen atom, R⁶ represents a hydrogen atomor a carboxyl-protecting group, a, b, and c each represents an integerof 0 or 1, the bond shown with a wavy line represents a bond ofanti-form or syn-form, the bond shown with a straight line and a dottedline represents a double bond or a single bond, X represents a hydrogenatom, a hydroxyl group or a group: ##STR2## wherein R⁷ represents ahydrogen atom, a chlorine atom, a carboxyl group, a methyl group, anisopropyl group, a hydroxy group, a methoxy group, or an acetoxy group,R⁸ and R⁹ are the same or different and represent hydrogen atoms,chlorine atoms, methyl groups, hydroxy groups, methoxy groups, ethoxygroups, acetoxy groups, chloroacetoxy groups, butanoyloxy groups,methanesulfonyloxy groups, p-toluenesulfonyloxy groups, amino groups,acetamino groups, benzyloxycarbonylamino groups, nitro groups,methanesulfonyl groups, together an ethylenedioxy group, or together acarbonyldioxy group, R¹⁰ represents a hydrogen atom, a hydroxy group, anacetoxy group, a methyl group, a methoxy group, a nitro group, or achloroacetoxy group, Z represents a carbon atom or a nitorgen atom, drepresents an integer of 0 or 1, and Y represents a halogen atom, anacetoxy group or a group: ##STR3## wherein R¹¹ represents a hydrogenatom, a carboxyl group, or a protected carboxyl group, R¹² represents ahydrogen atom or a carboxyl-protecting group, R¹³ represents a methylgroup, a hydroxy group, a carboxyl group, a carboxymethyl group, aprotected carboxyl group, or a protected carboxymethyl group, and R¹⁴represents a hydrogen atom, a carboxyl group, a hydroxysulfonyl group, aprotected carboxyl group, or a protected hydroxysulfonyl group.

The present invention is also directed to a process for preparingabove-mentioned cephalosporin derivatives. The present invention isfurther directed to pharmaceutical compositions for treating and/orpreventing infectious diseases characterized by containing thesecephalosporin derivatives as active components.

In the cephalosporin derivatives of the present invention represented bythe general formula (I), it is known that the aminothiazole moiety asthe substituent at the 7-position thereof exhibits tautomerism as shownbelow: ##STR4## wherein R¹, R², R³, R⁴, R⁵, a, b, c, X, the bond shownwith a wavy line, and the bond shown with a straight line and a dottedline have the same significance as defined above. In the presentinvention, the aminothiazole moiety is expressed as including bothisomers since both are generally deemed to be the same substance.Accordingly, the compounds of the present invention represented by thegeneral formula (I) also include both of these tautomeric isomers.

The compounds represented by the general formula (I) may form acid orbase addition salts. Typical examples of base addition salts of thecompounds represented by the general formula (I) includepharmacologically acceptable salts such as alkali metal salts such assodium salts, potassium salts, etc.; alkaline earth metal salts such ascalcium salts, etc.; salts of organic bases such as ammonium salts,benzylamine salts, diethylamine salts, etc.; salts of amino acids suchas arginine salts, lysine salts, etc. These salts of the compounds maybe a mono-salts, disalts or tri-salts. In the case of mono-salts ordisalts, the salts may be salts of the carboxyl group at the 2-positionand/or salts of the carboxyl or sulfoxy group contained in thesubstituents at the 3-position, and/or salts of the carboxyl group inthe acyl group at the 7-position, of the cephem skeleton.

Typical examples of acid addition salts of the compounds represented bythe general formula (I) include pharmacologically acceptable salts, suchas salts of inorganic acids such as hydrochlorides, hydrobromides,sulfates, phosphates, etc.; salts of organic acids such as acetates,citrates, maleates, tartarates, benzoates, ascorbates, ethanesulfonates,toluenesulfonates, etc.; salts of amino acids such as aspartates,glutamates, etc. The compounds of the present invention represented bythe general formula (I) may be present as a syn-isomer shown below:##STR5## wherein R¹, R², R³, R⁴, R⁵, a, b, c, X and the bond shown witha wavy line have the same significance as defined above; or as ananti-isomer shown below: ##STR6## wherein R¹, R², R³, R⁴, R⁵, a, b, c, Xand the bond shown with a wavy line have the same significance asdefined above; or as a mixture of these isomers. Among them, thesyn-isomer is particularly preferred and, mixtures mainly composed ofthe syn-isomer are also preferred.

In the compounds of the present invention represented by the generalformula (I), the amino-protecting groups may be selected from acylgroups such as formyl, acetyl, chloroacetyl, t-butoxycarbonyl,benzyloxycarbonyl, etc.; or aralkyl groups such as benzyl,diphenylmethyl, triphenylmethyl, etc. Trimethylsilyl group may also beused as an amino-protecting group. The carboxyl-protecting groups may beselected from alkyl esters such as methyl ester, ethyl ester, t-butylester, etc.; or aralkyl esters such as benzyl ester, diphenylmethylester, triphenylmethyl ester, etc.; or trimethylsilyl ester. Inorganicor organic bases may also be used as carboxyl-protecting groups.Collectively taking account of various operations, synthesis of thusprotected products, and conditions for the removal of protecting groups,it is preferred to use a triphenylmethyl group as the amino-protectinggroup and a diphenylmethyl group as the carboxyl-protecting group.

The compounds of the present invention represented by the generalformula (I) can be produced as follows. Namely;

PROCESS A

The compounds of the present invention represented by the generalformula (I) can be produced by reacting compounds represented by thegeneral formula (II): ##STR7## wherein R⁶ and Y have the samesignificance as defined above, the compounds represented by the generalformula (III): ##STR8## wherein R¹, R², R³, R⁴, R⁵, a, b, c, X, the bondshown with a wavy line and the bond shown with a straight line and adotted line have the same significance as defined above, and R¹⁵represents a hydrogen atom or a carboxyl-protecting group.

The compounds represented by the general formula (II) may be reactedwith the compounds represented by the general formula (III) usingsuitable condensing agents, for example, N,N-dicyclohexylcarbodiimide,N-ethyl-5-phenylisoxazolium-3'-sulfonate, etc. Alternatively, thecompounds represented by the general formula (III) may be converted intoappropriate reactive derivatives prior to the reaction with thecompounds represented by the general formula (II). The appropriatereactive derivatives may be, for example, acid halides (e.g., acidchlorides), azides, acid anhydrides, particularly mixed acid anhydridewith strong acids, active esters (e.g., N-hydroxysuccinimide ester) oractive amides (e.g., imidazolide, triazolide).

The reaction between the compounds represented by the general formula(II) and the compounds represented by the general formula (III) may becarried out generally in an inert organic solvent such as dioxane,tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethylacetate, dimethylformamide, etc., if necessary and desired, in thepresence of deacidifying agents. The reaction may also be carried out inan aqueous solution, preferably in the presence of deacidifying agents.As the deacidifying agents, triethylamine, diethylaniline, and the likemay be used in the organic solvent system, and aqueous alkalis,preferably sodium hydroxide, sodium hydrogen carbonate (sodiumbicarbonate), potassium carbonate, and the like may be used in theaqueous system.

The reaction may be carried out at temperatures ranging from about -30°C. to 30° C., and preferably from -10° C. to 10° C.

If necessary and desired, the protecting groups may be removed from thusobtained cephalosporin derivatives represented by the general formula(I).

The compounds represented by the general formula (II) used in theprocess of the present invention can be prepared by reacting known7-amino-cephalosporanic acid with heterocyclic thiols or pyridinederivatives corresponding to group Y, for example,2-carboxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine (Japanesepatent application No. 247251/1983corresponding to European patentapplication No. 150,507) or carboxyl-protected derivatives thereof, in asolvent such as alcohols, dimethylformamide, acetonitrile, or water etc.In the case that the reaction is carried out in organic solvents, it ispreferred that the reaction be performed in the presence of Lewis acidssuch as boron trifluoride-ether complexes, etc. Further in the case thatwater is used as the solvent, the reaction can be carried out in thepresence of an appropriate amount of aqueous alkalis such as sodiumhydrogen carbonate, potassium carbonate, etc., or using buffers having apH of 6.0 to 7.8 as the solvent.

The reaction temperature may be in the range of about 40° C. to about80° C., and preferably from 55° C. to 65° C.

If necessary and desired, the protecting groups may be removed from thusobtained compounds represented by the general formula (II).

PROCESS B

The compounds represented by the general formula (I) can be produced byreacting compounds represented by the general formula (IV): ##STR9##wherein R¹, R², R³, R⁴, R⁵, a, b, c, X, the bond shown with a wavy lineand the bond shown with a straight line and a dotted line have the samesignificance as defined above, and Q represents a chlorine atom, abromine atom, an iodine atom, or an acetoxy group, with compoundsrepresented by the general formula (V):

    H--Y                                                       (V)

wherein Y has the same significance as defined above.

The reaction between the compounds represented by the general formula(IV) and the compounds represented by the general formula (V) may becarried out in an organic solvent such as alcohols, dimethylformamide,dimethylsulfoxide, dichloromethane, etc. or mixture thereof, or in anaqueous system. Preferably, the reaction of the compounds represented bythe general formula (IV) wherein Q represents an acetoxy group, and thecompounds represented by the general formula (V) may be carried out inthe presence of an appropriate amount of aqueous alkalis, e.g., sodiumhydrogen carbonate or potassium carbonate, or carried out in a buffersolution at a pH in the range of 6.0 to 7.8, at temperatures in therange of about 40° C. to about 80° C., and preferably at from 55° to 65°C. Preferably, the reaction of the compounds represented by the generalformula (IV) wherein Q represents a halogen atom, and the compoundsrepresented by the general formula (V) may be carried out in an organicsolvent at temperatures in the range of about -30° C. to 30° C., andpreferably at from -10° C. to 10° C.

If necessary and desired, the protecting groups may be removed from thusobtained cephalosporin derivative represented by the general formula(I).

The compounds represented by the general formula (IV) wherein Qrepresents an acetoxy group or a chlorine atom, used in the process ofthe present invention can be prepared by reacting the compoundsrepresented by the general formula (III) with known7-amino-cephalosporanic acid or carboxyl-protected derivatives thereof,or with known 3-chloromethyl-7-amino-cephalosporanic acid orcarboxyl-protected derivatives thereof by the same manner as describedin Process A. the compounds represented by the general formula (IV)wherein Q represents a bromine atom or an iodine atom can be prepared byreacting the compounds represented by the general formula (IV) wherein Qrepresents a chlorine atom with alkali bromides or iodides such aspotassium bromide, potassium iodide, sodium bromide or sodium iodide inan inert organic solvent such as acetone or methylethylketone. Ifnecessary and desired, the reaction may be carried out in the darkness.The reaction temperature may be in the range of about -10° C. to 50° C.and preferably 0° C. to 20° C. If necessary and desired, the protectinggroups may be removed from thus obtained cephalosporin derivativesrepresented by the general formula (IV).

PROCESS C

The compounds represented by the general formula (I) can be produced byreacting compounds represented by the general formula (VI) ##STR10##wherein R¹, R⁶, Y, a, the bond shown with a wavy line and the bond shownwith a straight line and a dotted line have the same significance asdefined above, with compounds represented by the general formula (VII)##STR11## wherein R², R³, R⁴, R⁵, b, c and X have the same significanceas defined above. The reaction can be carried out by reacting thecompounds represented by the general formula (VII) with the compoundsrepresented by the general formula (VI) using a suitable condensingagent such as N,N-dicyclohexylcarbodiimide, triphenylphosphine, diethylazodicarboxylate, or by reacting the compounds represented by thegeneral formula (VI) with appropriate reactive derivatives of thecompounds represented by the general formula (VII); when the compoundsrepresented by the general formula (VII) are acids, they may beconverted into acid halides, acid anhydrides or mixed acid anhydrideswhich are preferably prepared with strong acids, and when the compoundsrepresented by the general formula (VII) are alcohols, they may beconverted into alkyl halides or aralkyl tosylates. In view ofreactivity, operability, etc., particularly preferred is the process inwhich the compounds represented by the general formula (VII) areconverted into acid halides or aralkyl halides, and reacted with thecompounds represented by the general formula (VI).

The reaction between the compounds represented by the general formula(VI) and the compounds represented by the general formula (VII) may becarried out generally in an inert organic solvent such as dioxane,tetrahydrofuran, acetonitrile, chloroform, methylene chloride, acetone,ethyl acetate, or dimethylformamide or in water or in water containingorganic solvents, preferably in the presence of deacidifying agents. Asthe deacidifying agents, triethylamine, diethylamine, etc. may be usedin an organic solvent system, and aqueous alkalis, preferably, sodiumhydrogen carbonate, sodium carbonate, potassium carbonate, etc. may beused in an aqueous system.

The reaction may be carried out at temperatures ranging from about -30°C. to 30° C., and preferably at from -10° C. to 10° C.

If necessary and desired, the protecting groups may be removed from thusobtained cephalosporin derivatives represented by the general formula(I).

The compounds represented by the general formula (VII) may be preparedfrom corresponding precursor by oxidation. For example,3,4-diacetoxy-2-methyl benzoic acid can be prepared from3,4-diacetoxy-2-methyl acetophenone by haloform reaction;3,4-carbonyldioxymandelic acid or 3,4-dihydroxymandelic acid can beprepared from piperonal by conversion intoα-chloro-3,4-carbonyldioxyphenylacetic acid, followed by hydroxylation.

PROCESS D

The compounds represented by the general formula (III) can be producedby reacting known compounds represented by the general formula (VIII):##STR12## wherein R¹ and R¹⁵ have the same significance as definedabove, with compounds represented by the formula (IX): ##STR13## whereinR², R³, R⁴, R⁵, b, c and X have the same significance as defined above.

The reaction between the compounds represented by the general formula(VIII) and the compounds represented by the general formula (IX) may becarried out generally in an inert solvent such as alcohols, dioxane,tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethylacetate, dimethylformamide, etc. and, if necessary, using suitabledehydrating agents, e.g., moleculr sieves.

The reaction may be carried ut at temperatures ranging from about 0° C.to 50° C., and preferably at from 10° C. to 30° C.

If necessary and desired, the protecting groups may be removed from thusobtained aminothiazole acetic acid derivatives represented by thegeneral formula (III).

The compounds represented by the general formula (IX) can be prepared byreacting corresponding halides represented by the general formula (X):##STR14## wherein R², R³, R⁵, b, c and X have the same significance asdefined above, and A represents a halogen atom, withN-hydroxyphthalimide, followed by the removal of the phthaloyl groupwith appropriate deprotecting agents such as N-methylhydrazine,hydrazine hydrate, etc.

The aforementioned halides represented by the general formula (X) can beprepared by halogenation of corresponding precursor. For example,α-bromodiacetoxyphenyl acetic acid can be prepared from diacetoxyphenylacetic acid by conversion into the acid halide and following brominationwith N-bromosuccinimide; α-chloro-3,4-carbonyldioxyphenyl acetic acidcan be prepared from piperonal by conversion into3,4-methylenedioxymandelic acid with bromoform followed by phosphoruspentachloride treatment; 4,5-diacetoxy-2-methylbenzoyl chloride can beprepared frm 4,5-diacetoxy-2-methylbenzoic acid with thionyl chloride.

PROCESS E

The compounds represented by the general formula (III) can be producedby reacting compounds represented by the general formula (XI): ##STR15##wherein R¹, R¹⁵, a, the bond shown with a wavy line and the bond shownwith a straight line and a dotted line have the same significance asdefined above, with compounds represented by the general formula (VII):##STR16## whrein R², R³, R⁴, R⁵, b, c and X have the same significanceas defined above.

The reaction between the compounds represented by the general formula(XI) and the compounds represented by the general formula (VII) may becarried out in the same manner as described in Process C.

If necessary and desired, the protecting groups may be removed from thethus obtained amino thiazole derivatives represented by the generalformula (III).

PROCESS F

The compounds represented by the general formula (III) can be producedby reacting compounds represented by the general formula: ##STR17##wherein R², R³, R⁴, R⁵, R¹⁵, a, b, c, X and the bond shown with a wavyline have the same significance as defined above, and R¹⁶ represents ahalogen atom, with compounds represented by the general formula (XIII):##STR18## wherein R¹ has the same significance as defined above.

The reaction between the compounds represented by the general formula(XII) and the compounds represented by the general formula (XIII) may becarried out generally in an inert solvent such as methanol, ethanol,isopropanol, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, ordimethylformamide, etc. If necessary, the reaction may be carried out inthe presence of deacidifying agents, such as triethylamine,diethylamine, sodium hydrogen carbonate, sodium carbonate, potassiumcarbonate, etc.

The reaction may be carried out at temperatures ranging from about -10°C. to 30° C., and preferably at from -10° C. to 10° C.

If necessary and desired, the protecting groups may be removed from thusobtained aminothiazole acetic acid derivatives represented by thegeneral formula (III).

The compounds represented by the general formula (XII) can be preparedby reacting the known compounds represented by the general formula (XIV)##STR19## wherein R¹⁵, R¹⁶ and the bond shown with a wavy line have thesame significance as defined above, with the compounds represented bythe general formula (VII) ##STR20## wherein R², R³, R⁴, R⁵, b, c and Xhave the same significance as defined above, in the same manner asdescribed in Process C.

To demonstrate the utility of the compounds of the present invention,data on antibacterial activity of representative compounds are shownbelow.

Compound 1:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4,5-trihydroxybenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 2:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-diacetoxy-2-methylbenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 3: (6R,7R)-7-[(2-amino-4-thiazolyl)-2-[Z-(4,5-dihydroxy-2-methylbenzoyl)oxyimino]acetamido-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid

Compound 4:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-dihydroxy-2-methylbenzoyl)oxyimino]acetamido-3-[(7-methyl-5H-5-oxo-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 5:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(4-acetoxy-2-carboxy-5-hydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 6:(6R,7R)-7-[(2-amino-4-thiazolyl)-2-[Z-[1-(3,4-dihydroxybenzoyl)-1-methylethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 7:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 8:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(R)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 9:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound10:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(R)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 11:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[1-carboxy-1-(3,4-dihydroxyphenyl)ethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 12:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4,5-trihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound13:(6R,7R)-7-[(2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(8-carboxytetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 14:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Compound 15:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate

Compound 16:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(2,3-cyclopentenopyridiniummethyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate

Compound 17:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(3,4-dihydroxybenzoylamino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

EXPERIMENTAL EXAMPLE 1

Antibacterial activity in vitro was determined in accordance with theagar plate dilution method.

A platinum loop each of test bacteria (10⁶ cells/ml), cultured inMueller Hinton broth, was inoculated on Mueller Hinton agar plates whichcontained test compounds at various concentrations. After cultivating at37° C. for 20 hours, the minimum inhibitory concentration (MIC μg/ml)was determined.

The results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    (MIC μg/ml)                                                                Com- Staphylococ-                                                                         Escheri-                                                                           Serratia                                                                            Klebsiella                                                                          Pseudomonas                                                                          Bacteroi-                                 pound                                                                              cus aureus                                                                           chia coli                                                                          marcescens                                                                          pneumoniae                                                                          aeruginosa                                                                           des fra-                                  Number                                                                             Smith  67   IFO3759                                                                             IFO3317                                                                             IFO3445                                                                              gilis 5524                                __________________________________________________________________________    1    0.78   <0.05                                                                              <0.05 <0.05 3.13   N.D.                                      2    0.78   <0.05                                                                              <0.05 <0.05 0.20   N.D.                                      3    N.D.   <0.05                                                                              <0.05 <0.05 0.20   N.D.                                      4    0.39   0.78 <0.05 <0.05 3.13   N.D.                                      5    1.56   <0.05                                                                              <0.05 <0.05 0.20   N.D.                                      6    6.25   <0.05                                                                              <0.05 <0.05 0.78   N.D.                                      7    N.D.   0.20 0.10  <0.05 1.56   N.D.                                      8    N.D.   0.20 0.10  <0.05 3.13   N.D.                                      9    0.78   0.10 0.05  <0.05 1.56   6.25                                      10   0.78   0.20 0.10  <0.05 6.25   N.D.                                      11   0.78   <0.05                                                                              0.20  <0.05 0.78   N.D.                                      12   0.78   0.10 N.D.  <0.05 6.25   N.D.                                      13   1.56   0.20 0.20  <0.05 0.78   N.D.                                      14   0.78   0.39 0.39  0.10  1.56   N.D.                                      15   0.78   0.10 0.10  <0.05 0.39   N.D.                                      16   0.78   0.10 0.10  <0.05 0.39   N.D.                                      17   3.13   <0.05                                                                              < 0.05                                                                              <0.05 1.56   N.D.                                      __________________________________________________________________________     N.D.; Not determined.                                                    

EXPERIMENTAL EXAMPLE 2

Protection ability against systemic infection was determined as follows.An aqueous suspension of test bacteria was intraperitoneally injectedinto 10 four week old ICR mice. One hour after the infection, testcompounds were intravenously administered. The number of surviving micewas counted 1 week after injection to determine the dose at which 50% ofthe test animals were alive (ED₅₀ : mg/kg).

The results are shown in Table 2-a through 2-b.

                  TABLE 2-a                                                       ______________________________________                                                           ED.sub.50 (mg/Kg)                                                             Serra-    Pseudo-                                                     Esche-  tia       monas  Staphylo-                                            richia  marces-   aerugi-                                                                              coccus                                    Compound   coli    cenes     nosa   aureus                                    Number     111     274       IFO3445                                                                              242*                                      ______________________________________                                        2          2.28    3.08      212    7.90                                      3          N.D     1.73      407    1.79                                      CAZ**      6.55    4.23      229    >100                                      CMD***     N.D.    N.D.      N.D.   31.0                                      ______________________________________                                         N.D.;Not determined.                                                          *;Methicillinresistant strain                                                 **;Ceftazidime                                                                ***;Cefamandole                                                          

                  TABLE 2-b                                                       ______________________________________                                                           ED.sub.50 (mg/Kg)                                                             Serra-    Pseudo-                                                     Esche-  tia       monas  Staphylo-                                            richia  marces-   aerugi-                                                                              coccus                                    Compound   coli    cenes     nosa   aureus                                    Number     111     274       IFO3445                                                                              242*                                      ______________________________________                                        5          N.D.    2.56      N.D.   12.4                                      8          N.D.    10.5      N.D.   N.D.                                      9          1.73    0.47      95.0   3.34                                      10         N.D.    28.6      N.D.   N.D                                       13         N.D.    1.05      N.D.   N.D.                                      CAZ**      3.91    6.41      230    >2100                                     CMD***     N.D.    N.D.      N.D.   8.94                                      ______________________________________                                         N.D.;Not determined.                                                          *;Methicillinresistant strain                                                 **;Ceftazidime                                                                ***;Cefamandole                                                          

Next, LD₅₀ of representative examples of the compounds of the presentinvention is shown in Table 3 wherein LD₅₀ was determined in accordancewith the Probit method.

                  TABLE 3                                                         ______________________________________                                        Compound No.  LD.sub.50 (mg/Kg, i.v.)                                         ______________________________________                                        1             >1000                                                           2             >1000                                                           4             >1000                                                           6             >1000                                                           9             >1000                                                           13            >1000                                                           15            >1000                                                           16            >1000                                                           ______________________________________                                    

The compounds of the present invention are active againstmicroorganisms, such as Gram-positive aerobic bacteria such asStaphylococcus aureus, streptococci, etc., Gram-negative aerobicbacteria such as Escherichia coli, Klebsiella pneumoniae, Proteusmirabilis, Proteus morganii, Serratia marcescens, Pseudomonasaeruginosa, Citrobacter, Enterbacter, Flavobacter, etc. and anaerobicbacteria such as Peptococci, Peptostreptococci, Bacteroides, etc., andare extremely useful for the treatment of infectious diseases such asbrain abscess with Staphylococcus aureus, bacterial meningitis andpurulent meningitis with Escherichia coli, Hemophilus influenzae, andStreptococcus pneumoniae, infective endocarditis with Streptococcusepidermidis, Staphylococcus aureus, and Klebsiella pneumoniae, pneumoniawith Pseudomona aeruginosa, Hemophilus influenzae, Klebsiellapneumoniae, and Staphylococcus aureus, and pyelonephritis withEscherichia coli, Klebsiella, Proteus and Pseudomonas etc.

The cephalosporin derivatives provided by the present invention can beemployed as pharmaceutical compositions, for example, in the form ofpharmaceutical compositions containing cephalosporin derivativestogether with appropriate, pharmaceutically acceptable carriers. Thepharmaceutical composition may take a solid form (for example, tablets,capsules, etc.) or a liquid form (for example, injections, etc.). Thecompositions may be sterilized and may contain auxiliary agentsgenerally employed in the pharmaceutical art.

Further, it is preferred to use the compounds after they are formed intofreeze-dried products or powders followed by dissolving them in aconventional solvent, e.g., water or physiological saline, for use. Thecompounds can be used orally or parenterally. While dose variesdepending upon age and conditions of the patient, conditions and kind ofdiseases, etc., from about 0.1 to about 10 g, preferably from about 0.2to about 5 g, can be used as a daily dose for an adult. Parenteraladministration of the compounds provided by the present invention isparticularly preferred.

Hereafter the present invention will be described with reference to theexamples below but is not deemed to be limited thereof.

EXAMPLE 1 Preparation of (6R,7R) -7-[(2-(2-amino-4-thiazolyl)-2-[Z-(3,4,5-trihydroxybenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 1)

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-3,4,5-tris(chloroacetoxy)benzoyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (0.7 g) in dry dichloromethane (17 ml) wasadded potassium carbonate (0.1 g) all at once, followed by dropwiseaddition of a solution of 3,4,5-tris(chloroacetoxy)benzoyl chloride(0.376 g) in dry dichloromethane (10 ml) over a period of five minutes,and the yellow mixture was stirred at 0° C. for 30 minutes. Afterfiltering off the insoluble matters, the filtrate was concentrated underreduced pressure, and the yellow residue was crystallized with ether (50ml), giving 0.92 g of the objective compound as pale yellow crystals.

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[3,4,5-tris(chloroacetoxy)benzoyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 1 (0.9 g) indichloroethane (7 ml) were added anisole (0.4 ml) and trifluoraceticacid (0.8 ml) containing a little water under ice cooling, and theresulting yellow solution was stirred at room temperature for two hours.After removing the solvent by decantation, the residue was washed withdichloroethane (10 ml) and crystallized with ether (20 ml) anddichloromethane (30 ml), giving 0.39 g of the objective compound as paleyellow crystals (as trifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1781, 1637, 1597, 1509, 1324, 1234, 1170, 1128.

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=8 Hz), 8.0 (2H, s), 7.4 (1H, s), 7.2(1H, s), 5.9 (1H, dd, J=5, 8 Hz), 5.3 (1H, d, J=5 Hz), 4.8 (2H, s), 4.7(4H, s), 4.5 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s)

Step 3:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4,5-trihydroxybenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 2 (0.3 g) indimethylacetamide (3 ml) was added thiourea (0.12 g), and the mixturewas stirred at room temperature for five hours. The resulting solutionwas poured into ether (80 ml), and the formed crystals were collected byfiltration, and purified by silica gel column chromatography, giving0.12 g of the objective compound as pale yellow crystals.

IR (KBr, cm⁻¹): 1772, 1743, 1685, 1637, 1598, 1509, 1315, 1180

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=8 Hz), 7.4 (1H, s), 7.1 (1H, s), 7.0(2H, s), 6.0 (1H, dd, J=5, 8 Hz), 5.3 (1H, d, 5 Hz), 4.5 (2H, brs), 3.7(2H, ABq), 2.6 (3H, s)

EXAMPLE 2 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-diacetoxy-2-methylbenzoyl)oxyimino]acetamino]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl[-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 2)

Step 1:

Preparation of (6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(4,5-diacetoxy-2-methylbenzoyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl[-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (0.7 g) in dry dichloromethane (10 ml) wasadded 4,5-diacetoxy-2-methylbenzoyl chloride (0.19 g) at once and thenpotassium carbonate (0.083 g). The yellow suspension was stirred at 0°C. for 30 minutes, the insoluble matters were removed by filtration, andthe filtrate was washed with brine and dried over anhydrous sodiumsulfate. The dried solution was concentrated under reduced pressure, andthe residue was crystallized with ether (20 ml), giving 0.80 g of theobjective compound as pale yellow crystals.

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-4,5-diacetoxy-2-methylbenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 1 (0.70 g) indichloroethane (7.0 ml) were added anisole (0.35 ml) and trifluoraceticacid (0.7 ml) under ice cooling, and the resulting yellow solution wasstirred at room temperature for two hours. After removing the solventunder reduced pressure, ether (20 ml) was added to the residue to give0.35 g of the objective compound as milky white crystals (astrifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1778, 1637, 1597, 1509, 1206, 1175, 1112.

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=[Hz), 7.7 (1H, s), 7.4 (1H, s), 7.3(1H, s), 7.1 (1H, s), 5.8 (1H, dd, J=6, 8 Hz), 5.3 (1H, d, J=6 Hz), 4.5(2H, brs), 3.6 (2H, ABq), 2.6 (3H, s), 2.28 (6H, s), 2.24 (3H, s).

EXAMPLE 3 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-dihydroxy-2-methylbenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 3)

Step 1:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[4,5-bis(chloroacetoxy)-2-methylbenzoyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylicacid diphenylmethyl ester

To an ice-cooled solution of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (1.0 g) in dry dichloromethane (24 ml) wasadded potassium carbonate (0.17 g) at once, followed by dropwiseaddition of a solution of 4,5-bis(chloroacetoxy)-2-methylbenzoylchloride (0.43 g) in dry dichloromethane (16 ml) over a period of tenminutes, and the mixture was stirred at 0° C. for three hours. Afterfiltering off the insoluble matters, the filtrate was washed twice withwater, once with brine, and dried over anhydrous magnesium sulfate. Thedried solution was concentrated under reduced pressure, and the residuewas crystallized with ether, giving 1.13 g of the objective compound aspale yellow crystals.

Step 2

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[4,5-bis(chloroacetoxy)-2-methylbenzoyl]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 1 (1.3 g) in dichlorethane(8.3 ml) were added anisole (0.56 ml) and trifluoracetic acid (1.13 ml)containing a little water under ice cooling, and the resulting yellowsolution was stirred at room temperature for three hours. After removingthe solvent by decantation, the residue was crystallized with ether,giving 0.57 g of the objective compound as pale yellow crystals (astrifluroacetic acid salt).

IR (KBr, cm⁻¹): 1781, 1685, 1597, 1509, 1201, 1182, 1125

NMR (DMSO-d₆, δ): 10.1(1H, d, J=9 Hz), 7.8 (1H, s), 7.4 (2H, s), 7.1(1H, s), 5.9 (1H, dd, J=5, 9 Hz), 5.2 (1H, d, J=5 Hz), 4.7 (2H, s), 4.6(2H, s), 4.5 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s), 2.5 (3H, s).

Step 3:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-dihydroxy-2-methylbenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl[-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 2 (0.56 g) indimethylacetamide (6 ml) was added thiourea (0.24 g), and the mixturewas stirred at room temperature for four hours. The resulting solutionwas concentrated to about one half of the initial volume under reducedpressure, and the concentrated solution was poured into ether. Afterremoving the solvent by decantation, the residue was treated withdichloromethane, and the formed yellow crystals were purified by silicagel column chromatography, giving 0.37 g of the objective compound aspale yellow crystals.

IR (KBr, cm⁻¹): 1778, 1735, 1506, 1509, 1245, 1207, 1129.

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=7 Hz), 7.4 (1H, s), 7.3 (1H, s), 7.2(1H, s), 6.7 (1H, s), 6.0 (1H, dd, J=5, 7Hz), 5.2 (1H, s), 4.5 (2H,brs), 3.8 (2H, ABq), 2.6 (3H, s), 2.4 (3H, s).

EXAMPLE 4 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[4,5-bis(chloroacetoxy)-2-methylbenzoyl]oxyimino]acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid

Step 1:

Preparation of(6R,7R)-7-amino-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a suspension of 7-aminocephalosporanic acid (12.24 g) and2-mercapto-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine (9 g) inacetonitrile was added boron trifluoride etherate (26 g), and themixture was stirred at 60° C. for three hours and then overnight at roomtemperature. Water (70 ml) was added to the solution, and the formedcrystals were collected by filtration and washed with water, acetone andether in this order, giving 4.9 g of the objective compound as palebrown crystals.

IR (KBr, cm⁻¹): 1801, 1696, 1570, 1561, 1506, 1472, 1467, 1407, 1393.

NMR (DMSO-d₆, δ): 6.3 (1H, s), 5.1 (1H, d, J=4 Hz), 4.9 (1H, d, J=4 Hz),4.4 (2H, ABq), 3.7 (2H, ABq), 2.3 (3H, s).

Step 2

Preparation of(6R,7R)-7-amino-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

To a suspension of the product obtained in Step 1 (4.9 g) in acetone (40ml) was added diphenyldiazomethane (8.2 g), and the mixture was stirredovernight at room temperature. After filtering off the insolublematters, the filtrate ws concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography, giving 2.94 gof the objective compound as yellow crystals.

NMR (DMSO-d₆, δ): 7.7-7.4 (10H, m), 6.9 (1H, s), 6.3 (1H, s), 5.7 (1H,d, J=4 Hz), 5.2 (1H, d, J=4 Hz), 4.3 (2H, ABq), 3.7 (2H, ABq), 2.3 (3H,s).

Step 3:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

The product obtained in Step 2 (3.25 g) and2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]aceticacid (5.64 g) were dissolved in dichloromethane (93 ml) andtetrahydrofurnan (93 ml) under a nitrogen stream, and the solution wascooled to 0° C. Dicyclohexylcarbodiimide (2.32 g) was added to thissolution by small portions, and the mixture was stirred overnight atroom temperature. After filtering off the insoluble matters, thefiltrate was concentrated under reduced pressure. The residue wasredissolved in ethyl acetate and the insoluble matters were filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography, giving 2.5 gof the objective compound as yellow crystals.

NMR (DMSO-d₆, δ): 9.5 (1H, d, J=8 Hz), 8.8 (1H, s), 7.7-7.2 (25H, m),6.9 (1H, s), 6.7 (1H, s), 6.3 (1H, s), 5.8 (1H, dd, J=5, 8 Hz), 5.2 (1H,d, 5 Hz), 4.3 (2H, ABq), 3.8 (2H, ABq), 3.1 (3H, s), 2.3 (3H, s), 1.4(6H, s).

Step 4:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To a solution of the product obtained in Step 3 (1.5 g) in acetone (12ml) was added 1N hydrochloric acid 2.6 ml), and the resulting solutionwas stirred at room temperature for 3.5 hours. Ethyl acetate was addedto the solution, and the organic layer was washed with water, 5% sodiumbicarbonate solution and brine in that order, and dried over anhydroussodium sulfate. The dried solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography, giving 1.06 g of the objective compound as milky whitecrystals.

NMR (DMSO-d₆, δ):

11.3 (1H, s), 9.5 (1H, d, J=8 Hz), 8.7 (1H, s), 7.6-7.2 (25H, m), 7.0(1H, s), 6.6 (1H, s), 6.2 (1H, s), 5.8 (1H, dd, J=4, 8 Hz), 5.2 (1H, d,J=4 Hz), 4.3 (2H, ABq), 3.7 (2H, ABq), 2.3 (3H, s).

Step 5

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[4,5-bis(chloracetoxy)-2-methylbenzoyl]oxyimino]acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the product obtained in Step 4 (0.6 g) indry dichloromethane (15 ml) was added potassium carbonate (0.1 g) atonce, followed by dropwise addition of a solution of4,5-bis(chloroacetoxy)-2-methylbenzoyl chloride (0.25 g) in drydichloromethane (10 ml). The mixture was stirred under ice cooling forone hour and then at room temperature for an additional two hours. Afterfiltering off the insoluble matters, the filtrate was washed with waterand with brine, and dried over anhydrous sodium sulfate. The driedsolution was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography, giving 0.47 g of theobjective compound.

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=8 Hz), 9.0 (1H, s), 7.8-7.1 (28H, m),7.0 (1H, s), 6.3 (1H, s), 5.8 (1H, dd, J=4, 8 Hz), 5.2 (1H, d, J=4 Hz),4.7 (2H, s), 4.5 (2H, s), 4.3 (2H, ABq), 3.6 (2H, ABq), 2.5 (3H, s), 2.3(3H, s).

Step 6

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[4,5-bix(chloroacetoxy)-2-methylbenzoyl]oxyimino]acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 5 (0.47 g) indichloroethane (3.5 ml) were added anisole (0.23 ml) and trifluoraceticacid (0.47 ml) under ice cooling, and the resulting solution was stirredat room temperature for five hours. After removing the solvent underreduced pressure, the residue was crystallizd with ether, giving 0.3 gof the objective compound (as trifluoracetic acid salt).

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=8 Hz), 7.8 (1H, s), 7.4 (1H, s), 7.2(1H, s), 6.3 (1H, s), 5.9 (1H, dd, J=4, 8 Hz), 5.2 (1H, d, J=4 Hz), 4.7(2H, s), 4.6 (2H, s), 4.4 (2H, brs), 3.7 (2H, ABq), 2.5 (3H, s), 2.3(3H, s)

EXAMPLE 5 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-dihydroxy-2-methylbenzoyl)oxyimino]acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid (Compound 4)

To a solution of the product obtained in Example 4 (0.2 g) indimethylformamide (3 ml) was added thiourea (0.13 g), and the mixturewas stirred at room temperature for 7 hours. Ether was added to thesolution, and the formed crystals were washed with dichloromethane, andpurified by silica gel column chromatography, giving 0.7 g of theobjective compound as milky white crystals.

IR (KBr, cm⁻¹): 1773, 1685, 1677, 1648, 1637, 1507, 1474.

NMR (DMSO-d₆, δ): 10.1 (1H, d, J=8 Hz), 7.3 (1H, s), 7.1 (1H, s, 6.7(1H, s), 6.3 (1H, s), 5.9 (1H, dd, J= 4, 8 Hz), 5.2 (1H, d, J=4 Hz), 4.4(2H, brs), 3.6 (2H, ABq), 2.4 (3H, s), 2.3 (3H, s).

EXAMPLE 6 Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(4-acetoxy-2-carboxy-5-hydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5methyl-s-triazolo-[1,5a)]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 5)

Step 1

Preparation of 2-bromomethyl-4,5-diacetoxybenzoic acid diphenylmethylester.

To a suspension of 4,5-diacetoxy-2-methylbenzoic acid (11.9 g) inbenzene (140 ml) were added thionyl chloride (14.3 ml) anddimethylformamdide (2 drops), and the mixture was stirred at 50° C.-70°C. for one hour. The solvent was removed under reduced pressure, and theresidue was redissolved in benzene and concentrated under reducedpressure to remove remaining thionyl chloride. The residue was refluxedwith benzene (240 ml), N-bromosuccinimide (8.45 g) and benzoylperoxide(230 mg) for two hours. Refluxing was continued for another two hoursafter addition of N-bromosuccinimide (8.45 g) and benzoylperoxide (230mg). The resulting solution was allowed to stand until it reached roomtemperature, and concentrated under reduced pressure. The residue wasdissolved in carbon tetrachloride and the insoluble matters wre filteredoff, and the filtrate was concentrated under reduced pressure. To asolution of the residue in dichloromethane (250 ml) were addeddiphenylmethanol (8.7 g) and pyridine (3.82 ml) under ice cooling, andthe solution was stirred overnight at room temperature. The resultingsolution was washed with 1 N hydrochloric acid and with brine, and driedover anhydrous sodium sulfate. The dried solution was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography, giving 8.8 g of the objective compound.

NMR (CDCl₃, δ) 7.9-7.2 (12H, m), 7.1 (1H, s), 5.0 (2H, s), 2.3 (6H, s)

Step 2:

Preparation of 5-acetoxy-4-hydroxy-2-N-phthaloyloxymethylbenzoic aciddiphenylmethyl ester

To a suspension of N-hydroxyphthalimide (2.9 g) in acetonitrile (100 ml)was added triethylamine (2.46 ml) under ice cooling. Then the productobtained in Step 1 (8.8 g) dissolved in acetonitrile (65 ml) was addeddropwise, and the mixture was stirred for 15 minutes under ice cooling.N-hydroxyphthalimide (2.9 g) was added and stirring was continued for anadditional 10 minutes. Resulting solution was poured into 1N citric acidsolution under ice cooling, and extracted twice with ethyl acetate. Theorganic layer was washed with saturated sodium bicarbonate solution,water and brine in that order, and dried over anhydrous sodium sulfate.The dried solution was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography, giving 3.03 gof the objective compound.

NMR (CDCl₃, δ): 7.9-7.2 (16H, m), 7.0 (1H, s), 5.6 (2H, s), 2.3 (3H, s).

Step 3

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[(4-acetoxy-5-hydroxy-2-diphenylmethyloxycarbonylphenyl)methyl]oxyimino]aceticacid

To a solution of the product obtained in Step 2 (1.5 g) indichloromethane (30 ml) was added methylhydrazine (0.15 ml) slowly undercooling at -60 ° C. The solution was stirred at -60° C. for ten minutesand at 0° C. for additional four hours. After filtering off theinsoluble matters, the filtrate was concentrated under reduced pressureand the residue was dissolved in methanol. This solution was added to asolution of (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (0.7 g)in methanol (40 ml), and the mixture was stirred at room temperature forone hour. The resulting solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography, giving 0.65 g of the objective compound as pale yellowcrystals.

NMR (DMSO-d₆, δ): 8.8 (1H, brs), 7.8-7.0 (28H, m), 6.8 (1H, s), 5.4 (2H,s), 2.3 (3H, s).

Step 4:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[(4-acetoxy-2-diphenylmethyloxycarbonyl-5-hydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the product obtained in Step 3 (0.63 g) and(6R,7R)-7-amino-3-[)2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (0.5 g) in dry dichloromethane (20 ml) wasadded dicyclohexylcarbodiimide (0.178 g), and the mixture was stirredovernight at room temperature. After filtering off the insolublematters, the filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography, giving 0.15 gof the objective compound.

NMR (DMSO-d₆, δ): 10.5 (1H, s), 9.6 (1H, d), 8.8 (1H, brs), 7.8 (1H, s),7.7-6.9 (50H, m), 6.8 (1H, s), 5.9 (1H, dd), 5.4 (2H, s), 5.3 (1H, d),4.3 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s), 2.3 (3H, s).

Step 5:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(4-acetoxy-2-carboxy-5-hydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To an ice-cooled solution of the product obtained in Step 4 (0.3 g) indichloroethane (5.5 ml) were added anisole (0.2 ml) and trifluroaceticacid (0.7 ml), and the mixture was stirred at room temperature for twohours. After removing the solvent by decantation, the residue was washedwith dichloroethane, and crystallized with ether, giving 0.105 g of theobjective compound as pale yellow crystals (as trifluoracetic acidsalt).

IR (KBr, cm³¹ 1): 1772, 1676, 1637, 1598, 1511, 1202.

NMR (DMSO-d⁶, δ): 9.7 (1H, d, J=8 Hz), 7.6 (1H, s), 7.4 (1H, s), 7.0(1H, s), 6.8 (1H, s), 5.9 (1H, dd, J=5, 8 Hz), 5.5 (2H, s), 5.2 (1H, d,J=5 Hz), 4.4 (2H, brs), 3.6 (2H, ABq), 2.6 (3H, s), 2.2 (3H, s).

EXAMPLE 7 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(1-(3,4-dihydroxybenzoyl)-1-methylethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 6)

Step 1:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[1-(3,4-diacetoxybenzoyl)-1-methylethyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazxolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To a solution of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-1-(3,4-diacetoxybenzoyl)-1-methylethyl]oxyimino]aceticacid (5.1 g) in dry dichloromethane (50 ml) were added(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (5.0 g) and tetrahydrofuran (50 ml). To themixture was added dicyclohexylcarbodiimide (1.5 g) under ice cooling,and stirring was continued at room temperature for three hours. Afterfiltering off the insoluble matters, the filtrate was concentrated underreduced pressure and ethyl acetate was added to the residue. Theinsoluble matters were filtered off, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, giving 3.85 g of the objective compound.

IR (KBr, cm⁻¹): 1781, 1735, 1686, 1596, 1508, 1372, 1242, 701.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=9 Hz), 8.9 (1H, s), 8.3-7.2 (40H, m),6.9 (1H, s), 6.7 (1H, s), 5.9 (1H, dd, J=5, 9 Hz), 5.3 (1H, d, J=5 Hz),4.4 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s), 2.3 (6H, s), 1.5 (6H, s).

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-1-(3,4-diacetoxybenzoyl)-1-methylethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To an ice-cooled solution of the product obtained Step 1 (3.8 g) indichloroethane (28 ml) were added anisole (1.95 ml) and trifluoroaceticacid (3.8 ml), and the mixture was stirred at room temperature for 3.5hours. After removing the solvent by decantation, the residue was washedtwice with dichloroethane, and crystallized with ether, giving 1.8 g ofthe objective compound (as trifluroacetic acid salt).

IR (KBr, cm⁻¹): 1774, 1685, 1636, 1598, 1509, 1373, 1203, 1112.

NMR (DMSO-d₆, δ): 9.,7 (1H, d, J=9 Hz), 8.1-7.3 (4H, m), 6.7 (1H, s),5.9 (1H, dd, J=5, 9 Hz), 5.2 (1H, d, J=5 Hz), 4.4 (2H, brs), 3.7 (2H,ABq), 2.6 (3H, s), 2.3 (6H, s), 1.5 (6H, s).

Step 3:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-1-(3,4-dihydroxybenzoyl)-1-methylethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 2 (0.6 g) was suspended in water (20 ml),and the pH of the suspension was adjusted to 8.0 with sodiumbicarbonate. After stirring at 30° C. for five hours, the resultingsolution was applied to a column of Diaion HP 10. The objectivefractions eluted with methanol/water were collected and lyophilized,giving 0.34 g of the objective compound (as sodium salt).

IR (KBr, cm⁻¹): 1772, 1598, 1513, 1406, 1363, 1189, 1163.

NMR (DMSO-d₆, δ): 9.6 (1H, d, J=9 Hz), 7.7-6.6 (4H, m), 6.6 (1H, s), 5.8(1H, dd, J=5, 9 Hz), 5.1 (1H, d, J=5 Hz), 4.6 (2H, ABq), 3.7 (2H, ABq),2.6 (3H, s), 1.5 (6H, s).

EXAMPLE 8 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 7)

Step 1

Preparation of 2-bromo-(3,4-diacetoxyphenyl)acetic acid

Thionyl chloride (60 ml) was added to a suspension of3,4-diacetoxyphenylacetic acid (51.1 g) in carbon tetrachloride (105 ml)and the mixture was heated at 70° C. for one hour. After cooling to roomtemperature, N-bromosuccinimide (42.3 g), carbon tetrachloride (105 ml)and a little amount of hydrobromic acid were added, and the mixture washeated for an additional one hour. The resulting mixture wasconcentrated under reduced pressure, and the residue was redissolved incarbon tetrachloride. After filtering off the insoluble matters, thefiltrate ws dissolved in acetone (400 ml) and the pH of the solution wasadjusted to 4.0 with saturated sodium bicarbonate aqueous solution underice cooling. The resulting mixture was extracted with chloroform. Thechloroform layer was washed with brine and dried over anhydrous sodiumsulfate. The dried solution was concentrated under reduced pressure,giving 61.4 g of the objective compound.

NMR (CDCl₃, δ): 9.0 (1H, brs), 7.5-7.1 (3H, m), 5.3 (1H, s), 2.3 (6H,s).

Step 2:

Preparation of 2-bromo-(3,4-diacetoxyphenyl)acetic acid diphenylmethylester

To a solution of the product obtained in Step 1 (61.4 g) in acetone (500ml) was added diphenyldiazomethane, and the solution was stirred at roomtemperature for one hour. The resulting solution was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography, giving 48.4 g of the objective compound.

IR (KBr, cm⁻¹): 1772, 1756, 1752, 1505, 1371, 1259, 1212, 1113, 701.

NMR (CDCl₃, δ): 7.4-7.1 (13H, m), 6.9 (1H, s), 5.4 (1H, s), 2.3 (6H, s).

Step 3:

Preparation of 2-N-phthaloyloxy-(3,4-diacetoxyphenyl)acetic aciddiphenylmethyl ester

To an ice-cooled suspension of N-hydroxyphthalimide (15.9 g) inacetonitrile (300 ml) were added triethylamine (13.6 ml) and a solutionof the product obtained in Step 2 (48.4 g) in acetonitrile (200 ml). Themixture was stirred under ice cooling for 1.5 hours. The resultingsolution was concentrated under reduced pressure and redissolved inethyl acetate. The solution was washed with water, 1N citric acidsolution and with brine in that order. The washed solution was driedover anhydrous sodium sulfate and concentrated under reduced pressure,and the residue was purified by silica gel column chromatography, giving15.3 g of the objective compound.

IR (KBr, cm⁻¹): 1772, 1735, 1506, 1371, 1260, 1209, 1186, 1114, 700.

NMR (CDCl₃, δ): 7.7 (4H, s), 8.0-7.1 (13H, m), 6.9 (1H, s), 2.3 (6H, s).

Step 4:

Preparation of 2-aminooxy-(3,4-diacetoxyphenyl)acetic aciddiphenylmethyl ester

To a solution of the product obtained in Step 3 (15.3 g) indichloromethane (200 ml) was added methylhydrazine (1.34 ml) slowly at-60° C., and the mixture was allowed to stand until room temperature wasreached. After stirring for two hours, methylhydrazine (0.07 ml) wasadded to the mixture, followed by stirring for an additional 30 minutes.The insoluble matters were filtrated off, the filtrate was concentratedunder reduced pressure, and the residue was purified by silica getcolumn chromatography, giving 8.7 g of the objective compound.

IR (KBr, cm⁻¹): 1772, 1752, 1506, 1371, 1256, 1210, 1180, 1113, 702.

NMR (CDCl₃, δ): 7.7-7.0 (13H, m), 6.9 (1H, s), 5.2 (1H, s), 2.27 (3H,s), 2.26 (3H, s).

Step 5:

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]aceticacid

To a solution of (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid(7.62 g) in methanol (400 ml) was added dropwise a solution of theproduct obtained in Step 4 (8.7 g) in methanol (150 ml). The mixture wasstirred at room temperature for 1.5 hours, and concentrated underreduced pressure, giving 16.0 g of the objective compound as crudeproduct.

IR (KBr, cm⁻¹): 1772, 1256, 1209, 1180, 754, 701.

NMR (DMSO-d₆, δ): 8.9 (1H, s), 7.8-7.2 (28H, m), 6.9 (1H, s), 6.8 (1H,s), 5.9 (1H, s), 2.3 (6H, s).

Step 6

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the crude product obtained in Step 5 (5.6g) and(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (5.0 g) in dichloromethane (170 ml) was addeddicyclohexylcarbodiimide (1.4 g), and the mixture was stirred at roomtemperature for five hours. After filtering off the insoluble matters,the filtrate was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and the insoluble matters were filtered off.The filtrate was washed with brine and dried over anhydrous sodiumsulfate. The dried solution was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography, giving0.73 g (less polar form) and 1.39 g (more polar form) of the objectivecompounds.

less polar form

IR (KBr, cm⁻¹): 1780, 1742, 1737, 1507, 1249, 1205, 1182, 700.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=8 Hz), 8.9 (1H, brs), 7.5-7.1 (50H, m),6.9 (1H, s), 6.82 (1H, s), 6.78 (1H, s), 5.9 (1H, s), 5.8 (1H, dd, J=4,8 Hz), 5.2 (1H, d, J=4 Hz), 4.3 (2H, brs), 3.6 (2H, ABg), 2.6 (3H, s),2.2 (6H, s).

more polar form

IR (KBr, cm⁻¹): 1780, 1742, 1596, 1507, 1450, 1372, 1205, 1182, 700.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=9 Hz), 8.9 (1H, s), 7.4-7.2 (50H, m),7.0 (1H, s), 6.82 (1H, s), 6.76 (1H, s), 5.9 (1H, s), 5.9 (1H, dd, J=4,9 Hz), 5.2 (1H, d, J=4 Hz), 4.3 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s),2.20 (6H, s)

Step 7:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the less polar form of the product obtained in Step 6(0.73 g) in dichloroethane (3 ml) were added anisole (0.4 ml) andtrifluoroacetic acid (0.8 ml) under ice cooling, and the resultingsolution was stirred at room temperature for three hours. Additionaltrifluoroacetic acid (0.6 ml) was added and the mixture was stirred foranother 30 minutes. After removing the solvent by decantation, theresidue was washed with dichloroethane and crystallized with ether,giving 0.3 g of the objective compound (as trifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1773, 1735, 1684, 1637, 1598, 1509, 1373, 1206, 1186.

NMR (DMSO-d₆, δ): 9.6 (1H, d, J=8 Hz), 7.6 -7.2 (4H, m), 6.8 (1H, s),5.8 (1H, dd, J=4, 8 Hz), 5.6 (1H, s), 5.2 (1H, d, J=4 Hz), 4.4 (2H,brs), 3.72 (1H, d, J=22 Hz), 3.48 (1H, d, 22 Hz), 2.6 (3H, s), 2.2 (6H,s).

[α]²⁵ -2.9° (c=1.0, methanol:acetone=1:1).

EXAMPLE 9 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 9)

The product obtained in Step 7 of Example 8 (0.27 g) was suspended inwater (11 ml), and the pH of the mixture was adjusted to 8.0 with sodiumbicarbonate. After stirring at room temperature for six hours, theresulting solution was applied to a Diaion HP 10 column. The objectivefractions eluted with water were collected and lyophilized, giving 0.14g of the objective compound (as sodium salt).

IR (KBr, cm⁻¹): 1763, 1599, 1514, 1474, 1404, 1360, 1314.

NMR (D₂ O, δ): 7.2 (1H, s), 7.0-6.8 (4H, m), 5.7 (1H, d, J=5 Hz), 5.4(1H, s), 5.0 (1H, d, J=5 Hz), 4.3 (2H, ABq), 3.4 (2H, ABq), 2.6 (3H, s).

[α]²⁵ +27.4° (c=1.0, water).

EXAMPLE 10 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(R)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3--[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Compound 10)

Step 1:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(R)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

To a solution of the more polar form of the product obtained in Step 6of Example 8 (1.3 g) in dichloroethane (6 ml) were added anisole (0.8ml) and trifluoroacetic acid (1.6 ml) under ice cooling, and theresulting solution was stirred at room temperature for 4 hours. Afteraddition of dichloroethane (6 ml), the solvent was removed bydecantation. The residue was washed with dichloroethane, andcrystallized with ether, giving 0.78 g of the objective compound (astrifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1773, 1735, 1683, 1636, 1598, 1509, 1373, 1205, 1185.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=9 Hz), 7.4-7.2 (4H, m), 6.8 (1H, s), 5.8(1H, dd, J=4, 9 Hz), 5.6 (1H, s), 5.2 (1H, d, J=4 Hz), 4.5 (2H, brs),3.79 (1H, d, J=17 Hz), 3.60 (1H, d, J=17 Hz), 2.6 (3H, s), 2.3 (6H, s).

[α]²⁵ -17.4° (c=1.0, methanol:acetone=1:1).

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(R)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 1 (0.5 g) was suspended in water (20 ml),and the pH of the mixture was adjusted to 7.6-8.0 with sodiumbicarbonate. After stirring at room temperature for six hours, theresulting solution was applied to a Diaion HP 10 column. The objectivefractions eluted with water were collected and lyophilized, giving 0.2 gof the objective compound (as sodium salt).

IR (KBr, cm⁻¹): 1763, 1601, 1516, 1474, 1404, 1358, 1314.

NMR (D₂ O, δ): 7.2 (1H, s), 7.0-6.9 (4H, m), 5.6 (1H, d, J=5 Hz), 5.4(1H, s), 5.0 (1H, d, J=5 Hz), 4.4 (2H, ABq), 3.4 (2H, ABq), 2.6 (3H, s).

[α]²⁵ +21.8° (c=1.0, water).

EXAMPLE 11 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Step 1:

Preparation of2-(2-amino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]aceticacid

To an ice-cooled solution of product obtained in Step 4 of Example 8(5.3 g) in dimethylformamide (18 ml) was added(2-aminothiazol-4-yl)glyoxylic acid (2.03 g), and the mixture wasstirred overnight at room temperature. The resulting solution was pouredinto ice water (100 ml), and the mixture was acidified (pH 2) with 1Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with brine and dried over anhydrous magnesium sulfate. Thedried solution was concentrated under reduced pressure, and the residuewas crystallized with ether, giving 6.30 g of the objective compound.

NMR (DMSO-d₆, δ): 7.5-7.2 (15H, m), 6.85 (1H, s), 6.83 (1H, s), 5.9 (1H,s), 2.3 (6H, s).

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution containing the product obtained in Step 1 (3.0g) and(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (3.75 g) in dichloromethane (100 ml) was addeddicyclohexylcarbodiimide (1.54 g), and the mixture was stirred at roomtemperature. After filtering off the insoluble matters, the filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography, giving 4.8 g of the objectivecompound.

NMR (DMSO-d₆, δ): 9.9 and 9.8 (1H, d, J=8 Hz), 7.4-6.8 (38H, m), 5.9(1H, m), 5.9 (1H, s), 5.3 and 5.2 (1H, d, J=5 Hz), 4.3 (2H, brs), 3.6(2H, ABq), 2.6 (3H, s), 2.3 (3H, s), 2.2 (3H, s).

Step 3:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 2 (0.87 g) indichloroethane (1.6 ml) were added anisole (0.8 ml) and trifluoroaceticacid (2.4 ml) under ice cooling, and the resultng solution was stirredat room temperature for two hours. After removing the solvent bydecantation, the residue was washed with dichloroethane and crystallizedwith ether, giving 0.6 g of the objective compound (as trifluoroaceticacid salt).

NMR (DMSO-d₆, δ): 9.8 and 9.6 (1H, d, J=8 Hz), 7.4-6.9 (4H, m), 6.83 and6.79 (1H, s), 5.8 (1H, m), 5.6 (1H, s), 5.2 (1H, m), 4.4 (2H, brs), 3.7(2H, ABq), 2.6 (3H, s), 2.26 (3H, s), 2.24 (3H, s).

Step 4

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 3 (0.25 g) was suspended in water (10 ml),and the pH of the mixture was adjusted to 8.0 with sodium bicarbonate.After stirring at room temperature for 6 hours, the resulting solutionwas applied to a Diaion HP 10 column. The objective fractions elutedwith water were collected and lyophilized, giving 0.14 g of theobjective compound (as sodium salt).

NMR (D₂ O, δ): 7.2-6.9 (5H, m), 5.7 (1H, m), 5.4 (1H, s), 5.0 (1H, m),4.3 (2H, ABq), 3.4 (2H, ABq), 2.6 (3H, s).

EXAMPLE 12 Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[1-caboxy-1-(3,4-dihydroxyphenyl)ethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 11)

Step 1

Preparation of α-bromo-α-methyl-3,4-diacetoxyphenylacetic aciddiphenylmethyl ester

To a suspension of α-methyl-3,4,-diacetoxyphenyl acetic acid (10.0 g) incarbon tetrachloride (10 ml) were added thionyl chloride (12 ml) and alittle amount of dimethylformamide, and the mixture was stirred at 70°C. for 30 minutes. The solvent was removed under reduced pressure, andthe residue was redissolved in carbon tetrachloride (20 ml). Thionylchloride (5 ml), N-bromosuccinimide (7.22 g) and hydrobromic acid (0.1ml) were added to the solution, and the mixture was stirred at 85° C.for 1.5 hours. After filtering off the insoluble matters, the filtratewas concentrated under reduced pressure. The residue was dissolved inacetone (60 ml), and the pH of the solution was adjusted to 5 withsaturated sodium bicarbonate solution under ice cooling, then to 1 with1N hydrochloric acid. The acidified mixture was extracted with ethylacetate (400 ml), and the extract was washed with brine and dried overanhydrous sodium sulfate. The dried solution was concentrated underreduced pressure, and the residue was dissolved in acetone (60 ml) anddiphenyldiazomethane (7.0 g) was added. The solution was stirredovernight and the resulting solution was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,giving 4.1 g of the objective compound.

NMR (CDCl₃, δ): 7.4 -7.0 (13H, m), 6.9 (1H, s), 2.28 (6H, s), 2.27 (3H,s)

Step 2:

Preparation of α-methyl-α-phthaloyloxy-3,4-diacetoxyphenylacetic aciddiphenylmethyl ester

To an ice-cooled solution of the produce obtained in Step 1 (4.1 g) wereadded N-hydroxyphthalimide (1.31 g) and then anhydrous potassiumcarbonate over a period of 10 minutes. After stirring at roomtemperature for 1.5 hours, the resulting solution was poured into 1Ncitric acid aqueous solution (100 ml) and extracted with ethyl acetate(100 ml). The extract was washed thrice with brine and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was purified by silica gel column chromatography, giving 1.3g of the objective compound.

IR (KBr, cm⁻¹): 1773, 1741, 1736, 1372, 1263, 1208, 1191, 1170, 1119,702.

NMR (CDCl₃, δ): 7.8 (4H, m), 7.4 -7.2 (13H, m), 6.9 (1H, s), 2.28 (3H,s), 2.27 (3H, s), 1.9 (3H, s).

Step 3:

Preparation of α-aminooxy-α-methyl-3.4-diacetoxyphenylacetic aciddiphenylmethyl ester

To a solution of the product obtained in Step 2 (1.3 g) in drydichloromethane (20 ml) was added methylhydrazine (0.2 g) at -70° C.under a nitrogen stream, and the solution was stirred at -70° C. for 10minutes and then at 0° C. for 40 minutes. After filtering off theinsoluble matters, the filtrate was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography, giving0.61 g of the objective compound.

NMR (CDCl₃, δ): 7.3-7.0 (13H, m), 6.9 (1H, s), 2.28 (3H, s), 2.26 (3H,s), 1.9 (3H, s).

Step 4:

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[1-diphenylmethloxycarbonyl-1-(3,4-diacetoxyphenyl)ethyl]oxyimino]aceticacid

To a solution of (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid(0.49 g) in methanol (25 ml) was added dropwise a solution of theproduct obtained in Step 3 (0.61 g) in methanol (10 ml). The mixture wasstirred at room temperature for 1.5 hours and concentrated under reducedpressure. The residue was purified by silica gel column chromatography,giving 0.8 g of the objective compound.

IR (KRr, cm⁻¹): 1773, 1751, 1743, 1262, 1209, 1168, 1115, 701.

NMR (DMSO-d₆, δ): 8.8 (1H, s), 7.3-7.1 (28H, m), 6.8 (1H, s), 6.7 (1H,s), 2.3 (6H, s), 1.9 (3H, s).

Step 5:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[1-diphenylmethyloxycarbonyl-1-(3,4-diacetoxyphenyl)ethyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the product obtained in Step 4 (0.8 g) and(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (0.7 g) in dichloromethane (30 ml) was addeddicyclohexylcarbodiimide (0.19 g), and the mixture was stirred overnightat room temperature. After filtering off the insoluble matters, thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography, giving 0.6 g of theobjective compound.

IR (KBr, cm⁻¹): 1791, 1774, 1741, 1736, 1507, 1207, 1171, 700.

NMR (DMSO-d₆, δ): 9.9 and 9.7 (1H, d, J=8 Hz), 8.9 (1H, s), 7.5-6.8(53H, m), 5.9-5.7 (1H, m), 5.2 (1H, d, J=5 Hz), 4.3 (2H, brs), 3.7 (2H,ABq), 2.6 (3H, s), 2.23 (3H, s), 2.19 (3H, s), 1.9 (3H, s).

Step 6:

Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[1-carboxy-1-(3,4-diacetoxyphenyl)ethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 5 (0.6 g) indichloroethane (1 ml) were added anisole (0.5 ml) and trifluoroaceticacid (1 ml) under ice cooling, and the mixture was stirred at roomtemperature for 2 hours. Trifluoroacetic acid (1 ml) was added again andthe mixture was stirred overnight at room temperature. After addition ofdichloroethane (20 ml) to the resulting solution, the solvent wasremoved by decantation, and the residue was crystallized with ether,giving 0.31 g of the objective compound (as trifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1772, 1735, 1683, 1636, 1597, 1509, 1263, 1232, 1203,1172.

NMR (DMSO-d₆, δ): 9.8-9.7 (1H, m), 7.4-7.0 (4H, m), 6.78 and 6.74 (1H,s), 5.8-5.7 (1H, m), 5.3-5.2 (1H, m), 4.4 (2H, brs), 3.7-3.6 (2H, m),2.6 (3H, s), 2.2 (6H, s), 1.8 (3H, brs).

Step 7:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[1-carboxy-1-(3,4-dihydroxyphenyl)ethyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 6 (0.28 g) was suspended in water (11 ml),and the pH of the mixture was adjusted to 8.5 with sodium bicarbonate.The mixture was stirred at room temperature for 5.5 hours, and theresulting solution was applied to a Diaion HP 10 column. The objectivefractions were collected and lyophilized, giving 0.094 g of theobjective compound (as sodium salt).

IR (KBr, cm⁻¹): 1772, 1596, 1509, 1404, 1395, 1389, 1355, 1311.

NMR (D₂ O, δ): 7.2-6.8 (5H, m), 5.8-5.7 (1H, m), 5.2-5.1 (1H, m), 4.5(2H, ABq), 3.5 (2H, ABq), 2.6 (3H, s), 1.8 (3H, s).

EXAMPLE 13 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4,5-trihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 12)

Step 1:

Preparation of α-bromo-3,4,5-triacetoxyphenylacetic acid diphenylmethylester

To a suspension of 3,4,5-triacetoxyphenylacetic acid (34.5 g) in carbontetrachloride (90 ml) were added thionyl chloride (32.5 ml) anddimethylformamide (0.2 ml) and the mixture was stirred at 60° C. for onehour, and cooled to room temperature. Then N-bromosuccinimide (23.7 g),carbon tetrachloride (60 ml) and a little amount of hydrobromic acidwere added and the mixture was stirred at 60° C. for three hours.Insoluble matters were filtered off, and the filtrate was concentratedunder reduced pressure. The residue was dissolved in acetone (200 ml)and the pH of the solution was adjusted to 5.0 with saturated sodiumbicarbonate solution, then to 1 with 1N hydrochloric acid under icecooling. The acidified mixture was diluted with water, and extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in acetone (200 ml) and diphenyldiazomethane (20.5g) was added. The solution was stirred at room temperature for one hour.The resulting solution was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography, giving 30 g ofthe objective compound.

NMR (DMSO-d₆, δ): 7.5-7.3 (12H, m), 6.9 (1H, s), 6.2 (1H, s), 2.3 (9H,s).

Step 2:

Preparation of α-N-phthaloyloxy-3,4,5-triacetoxyphenylacetic aciddiphenylmethyl ester

To an ice-cooled solution of N-hydroxyphthalimide (8.8 g) inacetonitrile (180 ml) was added triethylamine (7.5 ml), then a solutionof the product obtained in Step 1 (30 g) in acetonitrile (120 ml), andthe mixture was stirred under ice cooling for 15 minutes. Ethyl acetate(1.5 l) was added, and the resultant solution was washed with anice-cooled solution of 1N citric acid (600 ml) and brine, and dried overanhydrous sodium sulfate. The dried solution was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography, giving 10 g of the objective compound.

IR (KBr, cm⁻¹): 1782, 1735, 1372, 1208, 1187, 1054, 700.

NMR (DMSO-d₆, δ): 7.7 (4H, s), 6.9 (1H, s), 6.2 (1H, s), 2.32 (3H, s),2.29 (6H, s).

Step 3

Preparation of α-aminooxy-3,4,5-triacetoxyphenylacetic aciddiphenylmethyl ester.

To a solution of the product obtained in Step 2 (10 g) indichloromethane (120 ml) was added methylhydrazine (0.83 ml) slowly at-60° C., and the mixture was stirred at 0° C. for 40 minutes. Insolublematters were filtered off, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, giving 2.2 g of the objective compound.

NMR (CDCl₃, δ): 7.3-7.1 (12H, m), 6.9 (1H, s), 5.2 (1H, s), 2.27 (3H,s), 2.23 (6H, s).

Step 4

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4,5-triacetoxyphenyl)methyl]oxyimino]acetic acid

To a solution of (2-triphenylmethylaminothiazol-4-yl)glyoxylic acid (1.7g) in methanol (100 ml) was added dropwise a solution of the productobtained in Step 3 (2.2 g) in methanol (40 ml). The solution was stirredat room temperature for one hour, and the resulting solution wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, giving 2.2 g of the objective compound.

IR (KBr, cm⁻¹): 1780, 1752, 1496, 1370, 1206, 1186, 1053, 701.

NMR (DMSO-d₆, δ): 8.9 (1H, s), 7.3-7.2 (27H, m), 6.86 (1H, s), 6.83 (1H,s), 5.9 (1H, s), 2.30 (3H, s), 2.28 (6H, s).

Step 5:

Preparation of (6R,7R)-7-[2-(b2-triphenylmethylamino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4,5-triacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester

To an ice-cooled solution containing the product obtained in Step 4 (2.2g) and(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (1.84 g) in dichloromethane (65 ml) was addeddicyclohexylcarbodiimide (0.59 g), and the mixture was stirred overnightat room temperature. The insoluble matters were filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and the insoluble matters were removed byfiltration. The filtrate was washed with brine and dried over anhydroussodium sulfate. The dried solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography, giving 0.86 g (less polar form) and 0.94 g (more polarform) of the objective compound.

less polar form [(S)-isomer]

IR (KBr, cm⁻¹): 1782, 1742, 1521, 1508, 1498, 1371, 1185, 1054, 700.

NMR (DMSO-d₆, δ): 9.6 (1H, d, J=9 Hz), 8.7 (1H, s), 7.5-7.2 (49H, m),6.9 (1H, s), 6.83 (1H, s), 6.80 (1H, s), 5.9 (1H, s), 5.8 (1H, dd, J=5Hz, 9 Hz), 5.2 (1H, d, J=5 Hz), 4.3 (2H, brs), 3.6 (2H, ABq), 2.6 (3H,s), 2.20 (3H, s), 2.18 (6H, s).

more polar form [(R)-isomer]

IR (KBr, cm⁻¹): 1782, 1742, 1596, 1498, 1450, 1371, 744, 700.

NMR (DMSO-d₆, δ): 9.8 (1H, d, J=7 Hz), 8.9 (1H, s), 7.5-7.2 (49H, m),6.9 (1H, s), 6.82 (1H, s), 6.76 (1H, s), 5.9 (1H, s), 5.8 (1H, dd, J=5Hz, 7 Hz), 5.2 (1H, d, J=5 Hz), 4.3 (2H, brs), 3.6 (2H, ABq), 2.6 (3H,s), 2.3 (3H, s), 2.2 (6H, s).

Step 6:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4,5-triacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 5 as less polar form (0.8g) in dichloroethane (7 ml) were added anisole (0.36 ml) andtrifluoroacetic acid (0.73 ml) under ice cooling, and the resultingsolution was stirred at room temperature for three hours. The solventwas removed by decantation, and the residue was washed withdichloroethane (5 ml) and crystallized with ether, giving 0.45 g of theobjective compound (as trifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1774, 1676, 1630, 1597, 1509, 1193.

NMR (DMSO-d₆, δ): 9.5 (1H, d, J=9 Hz), 7.4 (1H, s), 7.3 (2H, s), 6.8(1H, s), 5.8 (1H, dd, J=5, 9 Hz), 5.6 (1H, s), 5.2 (1H, d, J=5 Hz), 4.4(2H, brs), 3.7 (2H, ABq), 2.6 (3H, s), 2.3 (9H, s).

Step 7:

Preparation of the (R)-isomer of the product obtained in Example 13,Step 6

The product obtained in Step 5 as more polar form was subjected to thesame process as described in Step 6, giving 0.25 g of the objectivecompound.

IR (KBr, cm¹): 1774, 1676, 1636, 1625, 1597, 1374, 1194.

NMR (DMSO-d₆, δ): 9.8 (1H, d, J=7 Hz), 7.4 (1H, s), 7.3 (2H, s), 6.8(1H, s), 5.8 (1H, dd, J=5, 7 Hz), 5.6 (1H, s), 5.2 (1H, d, J=5 Hz), 4.4(2H, brs), 3.7 (2H, ABq), 2.6 (3H, s), 2.3 (9H, s).

Step 8:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4,5-trihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 6 (0.43 g) was suspended in water (12 ml),and the pH of the mixture was adjusted to 8.0 with sodium bicarbonateunder a nitrogen stream. After stirring at room temperature for fivehours, the resulting solution was applied to a Diaion HP 10 column. Theobjective fractions eluted with water were collected and lyophilized,giving 0.15 g of the objective compound (as sodium salt).

IR (KBr, cm⁻¹): 1772, 1597, 1513, 1402, 1318.

NMR (D₂ O, δ): 7.2 (1H, s), 7.0 (1H, s), 6.6 (2H, s), 5.6 (1H, d, J=5Hz), 5.3 (1H, s), 5.0 (1H, d, J=5 Hz), 4.3 (2H, ABq), 3.4 (2H, ABq),2.6(3H, s)

Step 9:

Preparation of the (R)-isomer of the product obtained in Step 8

The product obtained in Step 7 as more polar form was subjected to thesame process as described in Step 8, giving 0.1 g of the objectivecompound (as sodium salt).

IR (KBr, cm⁻¹): 1773, 1596, 1517, 1311.

NMR (D₂ O, δ): 7.2 (1H, s), 7.0 (1H, s), 6.6 (2H, s), 5.6 (1H, d, J=4Hz), 5.3 (1H, s), 5.0 (1H, d, J=4 Hz), 4.4 (2H, ABq), 3.3 (2H, ABq), 2.6(3H, s).

EXAMPLE 14 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(8-carboxytetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 13)

Step 1:

Preparation of (6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(8-diphenylmethyloxycarbonyltetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution containing the product obtained in Step 5 ofExample 8 (1.0 g) and(6R,7R)-7-amino-3-[(8-diphenylmethyloxycarbonyltetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (0.90 g) in dichloromethane (50 ml) was addeddicyclohexylcarbodiimide (0.24 g), and the mixture was stirred overnightat room temperature. The insoluble matters were filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasredissolved in acetone and the insoluble matters were filtered off. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography, giving 0.75 g of theobjective compound.

IR (KBr, cm⁻¹): 1774, 1734, 1363, 1297, 1225, 1083, 700.

NMR (CDCl₃, δ): 8.1-6.7 (55H, m), 6.1 and 6.0 (1H, s), 5.9 (1H, m), 4.9(1H, m), 4.7 (2H, ABq), 3.2 (2H, ABq), 2.3 (6H, s).

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-[(8-carboxytetrazolo[1,5-b]pyridazin-6yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 1 (0.75 g) indichloroethane (3 ml) were added anisole (0.5 ml) and trifluoroaceticacid (3 ml) under ice cooling, and the resulting solution was stirred atroom temperature for 3.5 hours. The resultant solution was concentratedunder reduced pressure, and the residue was redissolved indichloroethane (15 ml). The solvent was removed by decantation, and theresidue was washed with dichloroethane (20 ml) and crystallized withether, giving 0.27 g of the objective compound (as trifluoroacetic acidsalt).

IR (KBr, cm⁻¹): 1773, 1676, 1638, 1374, 1208.

NMR (DMSO-d₆, δ): 9.7 (1H, m), 8.1 (1H, s), 7.4 -7.0 (3H, m), 6.81 and6.76 (1H, s), 5.8 (1H, m), 5.6 (1H, s), 5.1 (1H, m), 4.3 (2H, ABq), 3.6(2H, ABq), 2.3 (6H, s).

Step 3:

Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(8-carboxytetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 2 (0.25 g) was suspended in water (6 ml),and the pH of the mixture was adjusted to 8.5 with sodium bicarbonate.The mixture was stirred under nitrogen stream at room temperature for 5hours, and the resulting solution was applied to a Diaion HP 10 column.The objective fractions eluted with water were collected andlyophilized, giving 0.15 g of the objective compound (as sodium salt).

IR (KBr, cm⁻¹): 1766, 1589, 1388.

NMR (D₂ O, δ): 7.8 (1H, s), 7.2-6.8 (4H, m), 5.7 (1H, m), 5.4 (1H, s),5.0 (1H, m), 4.1 (2H, ABq), 3,4 (2H, ABq).

EXAMPLE 15 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(1-pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(Compound 14)

Step 1:

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution containing the product obtained in Step 5 ofExample 8 (3.0 g) and(6R,7R)-7-amino-3-acetoxymethyl-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (1.58 g) in dichloromethane (90 ml) was addeddicyclohexylcarbodiimide (0.74 g), and the mixture was stirred at roomtemperature for 4 hours. Insoluble matters were filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasredissolved in ethyl acetate and the insoluble matters were removed byfiltration. The filtrate was concentrated under reduced pressure and theresidue was purified by slica gel column chromatography, giving 2.42 gof the objective compound.

NMR (DMSO-d₆, δ): 9.7 (1H, m), 8.9 (1H, s), 7.6-6.8 (41H, m), 5.9 (1H,s), 5.8 (1H, m), 5.2 (1H, m), 4.8 (2H, ABq), 3.6 (2H, ABq), 2.3 (3H, s),2.2 (3H, s), 2.0 (3H, s)

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 1 (2.4 g) indichloroethane (18 ml) was added anisole (1.21 ml) and trifluoroaceticacid (2.42 ml) under ice cooling, and the resulting solution was stirredat room temperature for 5 hours. The resultant solution was concentratedunder reduced pressure, and the residue was crystallized with ether,giving 0.74 g of the objective compound (as trifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1773, 1684, 1637, 1374, 1219, 1213, 1210, 1184, 1114,

NMR (DMSO-d₆, δ): 9.7 (1H, m), 7.4-6.8 (4H, m), 5.8 (1H, m), 5.6 (1H,s), 5.1 (1H, m), 4.8 (2H, ABq), 3.5 (2H, ABq), 2.3 (6H, s), 2.0 (3H, s),

Step 3:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl0-2-[Z-[carboxy(3,4-dihydroxyphenyl)-methyl]oxyimino]acetamido]-3-(-pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

The product obtained in Step 2 (0.25 g) and pyridine were added to asolution of sodium iodide (0.76 g) in water (0.22 ml), and the mixturewas stirred at 50° C. for 1.5 hours. Acetone (10 ml) was then added tothe solution, and the formed crystals were collected by filtration. Thecrystals were dissolved in water, and the solution was applied to aDiaion HP 10 column. The objective fractions eluted with water werecollected and lyophilized, giving 0.05 g of the objective compound.

IR (KBr, cm⁻¹): 1772, 1624, 1533, 1397,

NMR (D₂ O, δ): 9.0-8.0 (5H, m), 7.2-7.0 (4H, m), 5.7-5.1 (5H, m), 3.4(2H, ABq),

EXAMPLE 16 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(Compound 15)

Step 1:

Preparation of 2-N-phthaloyloxy-(3,4-diacetoxyphenyl)acetic acid

To a suspension of the product obtained in Step 3 of Example 8 (102 g)in dichloroethane (150 ml) were added anisole (73 ml) andtrifluoroacetic acid (140 ml) under ice cooling, and the resultingmixture was stirred at 0° C. for one hour and then at room temperaturefor one hour. The solvent was removed under reduced pressure, and theresidue was washed with ether and hexane, then crystallized with ether,giving 59.4 g of the objective compound.

NMR (DMSO-d₆, δ): 7.8 (4H, s), 7.5-7.2 (3H, m), 5.8 (1H, s), 2.3 (6H,s),

Step 2:

Preparation of (S)-2-N-phthaloyloxy-(3,4-diacetoxyphenyl)acetic acid.

To a solution of the product obtained in Step 1 (61 g) in acetone (375ml) was added a solution of (R)-(+)-α-methylbenzylamine (18 g) inacetone (275 ml) at once, and the resulting solution was allowed tostand at room temperature for 2.5 hours. The formed crystals werecollected by filtration and washed with a small amount of acetone. Thecrystals were suspended in water and the pH of the suspension wasadjusted to 1 with 1 N hydrochloric acid. The resultant mixture wasextracted twice with ethyl acetate. The organic layer was washed withwater and brine, and dried over anhydrous sodium sulfate. The driedsolution was concentrated under reduced pressure, and the residue wascrystallized with ether and hexane, giving 12.7 g of the objectivecompound as milky white crystals.

NMR (CDCl₃, δ): 7.9-7.6 (4H, m), 7.5-7.2 (3H, m), 5.9 (1H, s), 2.28 (3H,s), 2.27 (3H, s),

Step 3:

Preparation of (S)-2-N-phthaloyloxy-(3,4-diacetoxyphenyl)acetic aciddiphenylmethyl ester

To an ice-cooled solution of the product obtained in Step 2 (22 g) inethyl acetate (600 ml) was added a solution of diphenyldiazomethane(27.9 g) in ethyl acetate (150 ml), and the resulting solution wasstirred at room temperature for one hour. The solvent was then removedunder reduced pressure, and the residue was washed with hexane andpurified by silica gel column chromatography, giving 26.3 g of theobjective compound as colorless crystals.

NMR (CDCl₃, δ): 7.8-7.6 (4H, m), 7.4-6.9 (14H, m), 6.0 (1H, s), 2.3 (6H,s),

Step 4:

Preparation of (S)-2-aminooxy-(3,4-diacetoxyphenyl)acetic aciddiphenylmethyl ester

To a solution of the product obtained in Step 3 (26.3 g) indichloromethane (370 ml) was added methylhydrazine (2.41 ml) slowly at-30° C. The mixture was left to stand until it reached room temperature,and stirring for three hours. The insoluble matters were filtered off,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, giving 20 g of thecompound as pale yellow oil.

NMR (CDCl₃, δ): 7.3-6.9 (14H, m), 5.2 (1H, s), 2.3 (6H, s),

Step 5:

Preparation of2-(2-amino-4-thiazolyl)-2-[Z-[(S)-diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]aceticacid

To an ice-cooled solution of the product obtained in Step 4 (20.3 g) indimethylformamide (60 ml) was added 2-(2-amino-4-thiazolyl)glyoxylicacid (7.8 g). the mixture was allowed to stand until it reached roomtemperature, and stirred overnight. The reaction mixture was then pouredinto ice-cooled water (400 ml), and the pH of the resulting mixture wasadjusted to 2.0 with 1 N hydrochloric acid. The mixture was extractedtwice with ethyl acetate (500 ml). The combined organic layer was washedwith brine (200 ml) and dried over anhydrous sodium sulfate. The driedsolution was concentrated under reduced pressure and the residue wasdissolved in a small amount of chloroform. This solution was addeddropwise to ether. The formed crystals were collected by filtration andwashed with ether, giving 22.3 g of the objective compound as paleyellow crystals.

NMR (DMSO-d₆, δ): 7.4-6.7 (15H, m), 6.0 (1H, s), 2.3 (6H, s),

Step 6

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-chloromethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid p-methoxybenzyl ester

To a suspension containing the product obtained in Step 5 (21.8 g) and(6R,7R)-7-amino-3chloromethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid p-methoxybenzyl ester p-toluenesulfonate (19.5 g) in drydichloromethane (250 ml) were added dicyclohexylamine (7.2 ml) anddiethylaniline (11.5 ml), and the mixture was cooled to -15° C. Asolution of phosphorus oxychloride (3.4 ml) in dry dichloromethane (30ml) was added dropwise to the suspension over a period of 40 minutes,and the mixture was stirred for 1.5 hours at -15° C. Ethyl acetate (1liter) was added, and the mixture was washed twice with 1 N hydrochloricacid (300 ml), twice with saturated sodium bicarbonate solution (200ml), then once with brine (300 ml), and dried over anhydrous sodiumsulfate. The dried solution was concentrated under reduced pressure, andthe residue was crystallized with ether, giving 29.9 g of the objectivecompound as pale yellow crystals.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=7 Hz), 7.5-6.8 (19H, m), 5.9 (1H, s),5.8 (1H, dd, J=5, 7 Hz), 5.2 (2H, brs), 5.1 (1H, d, J=5 Hz), 4.5 (2H,brs), 3.7 (3H, s), 3.5 (2H, ABq), 2.3 (6H, s),

Step 7:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-diphenylmethyloxycarbonyl-(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-iodomethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid p-methoxybenzyl ester

To a solution of the product obtained in Step 6 (14 g) in acetone (210ml) was added sodium iodide (4.85 g) in total darkness and the mixturewas stirred at room temperature for one hour. The reaction mixture wasthen poured into water (300 ml) and extracted twice with ethyl acetate(500 ml). The combined organic layer was washed with 5% sodiumthiosulfate solution (200 ml) and brine (200 ml), and dried overanhydrous sodium sulfate. The dried solution was concentrated underreduced pressure, giving 15.1 g of the objective compound as yellowcrystals.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=9 Hz), 7.4-6.8 (19H, m), 5.9 (1H, m),5.8 (1H, dd, J=5, 9 Hz), 5.1 (2H, brs), 5.1 (1H, d, J=5 Hz), 4.3 (2H,brs), 3.7 (3H, s), 3.6 (2H, ABq), 2.3 (6H, s),

Step 8:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-diphenylmethyloxycarbonyl-(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-(pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo]4.2.0]oct-2ene-2carboxylicacid p-methoxybenzyl ester iodide

To an ice-cooled solution of the product obtained in Step 7 (15.1 g) inthe mixture of dry dichloromethane (50 ml) and dry dimethyl sulfoxide(50 ml) was added dropwise a solution of pyridine (1.17 ml) in drydichloromethane (10 ml) over a period of 30 minutes, and the reactionmixture was stirred at 0° C. for 5 minutes, then at room temperature for1.5 hours. The resulting solution was poured into ether (1.5 liters) andthe solvent was removed by decantation. The residue was crystallizedwith ether (1 liter), giving 13.5 g of the objective compound as yellowcrystals.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=9 Hz), 9.0 (2H, m), 8.7 (1H, m), 8.2(2H, m), 7.4-6.8 (19H, m), 5.9 (1H, s), 5.8 (1H, dd, J=5, 9 Hz), 5.6(2H, brs), 5.2 (2H, brs), 5.1 (1H, d, J=5 Hz), 3.7 (3H, s), 3.6 (2H,ABq), 2.3 (3H, s), 2.2 (3H, s),

Step 9:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-(pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of the product obtained in Step 8 (13.4 g) indichloroethane (86 ml) were added anisole (10.7 ml) and trifluoroaceticacid (21.4 ml) under ice cooling, and the mixture was stirred at roomtemperature for 3.5 hours. The resulting solution was poured into ether(4 liter), and the formed crystals were collected by filtration, giving9.8 g of the objective compound (as trifluoroacetic acid salt).

NMR (DMSO-d₆, δ): 9.5 (1H, d, J=9 Hz), 9.0 (2H, m), 8.7 (1H, m), 8.2(2H, m), 7.4-6.8 (4H, m), 5.8 (1H, dd, J=5, 9 Hz), 5.60 (2H, brs), 5.58(1H, s), 5.2 (1H, d), 3.4 (2H, ABq), 2.27 (3H, s), 2.24 (3H, s),

Step 10:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylate

The product obtained in Step 9 (9.8 g) was suspended in water (255 ml)and the pH of the mixture was adjusted to 8.0-8.5 with sodiumbicarbonate under a nitrogen stream. The mixture was stirred overnightat room temperature, and the resulting solution was applied to a DiaionHP 10 column. The objective fractions eluted with 20% methanol in waterwere collected, concentrated to one third of its original volume underreduced pressure, and then lyophilized, giving 2.88 g of the objectivecompound (as sodium salt).

IR (KBr, cm⁻¹): 1773, 1624, 1609, 1533, 1389,

NMR (D₂ O, δ): 8.9 (2H, m), 8.5 (1H, m), 8.0 (2H, m), 6.9-6.7 (4H, m),5.7 (1H, d, J=5 Hz), 5.4 (1H, s), 5.3 (2H, ABq), 5.1 (1H, d, J=5 Hz),3.1 (2H, ABq),

EXAMPLE 17 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(2,3-cyclopentenopyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-carboxylate(Compound 16)

Step 1:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-diphenylmethloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-(2,3-cyclopentenopyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid p-methoxybenzyl ester iodide.

To an ice-cooled solution of the product obtained in Step 7 of Example16 (16 g) in the mixture of dry dichloromethane (50 ml) and dry dimethylsulfoxide (50 ml) was added dropwise a solution of2,3-cyclopentenopyridine (1.81 g) in dry dichloromethane (10 ml) over aperiod of 30 minutes, and the solution was stirred at 0° C. for 5minutes, then at room temperature for 2.5 hours. The resulting solutionwas poured into ether (2 liters) and the solvent was removed bydecantation. The residue was crystallized with ether (1 liter), giving14.5 g of the objective compound as yellow crystals.

NMR (DMSO-d₆, δ): 9.7 (1H, d, J=8 Hz), 8.4 (2H, m), 7.9 (1H, m), 7.4-6.7(19H, m), 5.90 (1H, dd, J=5, 8 Hz), 5.87 (1H, s), 5.5 (2H, brs), 5.2(2H, brs), 5.1 (1H, d, J=5 Hz), 3.7 (3H, s), 3.5-3.1 (6H, m), 2.26 (3H,s), 2.23 (3H, s), 2.20 (2H, m),

Step 2:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamido]-3-(2,3-cyclopentenopyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of the product obtained in Step 1 (14.5 g) indichloroethane (95 ml) were added anisole (11.6 ml) and trifluoroaceticacid (23.2 ml) under ice cooling, and the mixture was stirred at 0° C.for 5 minutes, then at room temperature for 3 hours. The resultingsolution was poured into ether (4 liters), and the formed crystals werecollected by filtration, giving 10.8 g of the objective compound (astrifluoroacetic acid salt).

NMR (DMSO-d₆, δ): 9.5 (1H, d, J=8 Hz), 8.6 (1H, m), 8.4 (1H, m), 7.9(1H, m), 7.4-6.8 (4H, m), 5.9 (1H, dd, J=5, 8 Hz), 5.6 (1H, s), 5.4 (2H,brs), 5.1 (1H, d), 3.4-3.0 (6H, m), 2.27 (3H, s), 2.24 (3H, s), 2.20(2H, m),

Step 3:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(2,3-cyclopentenopyridiniummethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

The product obtained in Step 2 (10.8 g) was suspended in water (270 ml),and the pH of the mixture was adjusted to 8.0-8.5 with sodiumbicarbonate under a nitrogen stream. The mixture was stirred overnightat room temperature, and the resulting solution was applied to a DiaionHP 10 column. The objective fractions eluted with 20% methanol in waterwere collected, concentrated to one third of its original volume underreduced pressure, and lyophilized, giving 2.49 g of the objectivecompound (as sodium salt).

IR (KBr, cm⁻¹): 1774, 1623, 1610, 1606, 1529, 1390,

NMR (D₂ O, δ): 8.5 (1H, m), 8.2 (1H, m), 7.7 (1H, m), 7.0-6.7 (4H, m),5.7 (1H, d, J=5 Hz), 5.4 (1H, s), 5.3 (2H, brs), 5.0 (1H, d, J=5 Hz),3.4-2.1 (8H, m)

EXAMPLE 18 Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(3,4-dihydroxybenzoylamino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylicacid (Compound 17)

Step 1:

Preparation of(6R,7R)-7-[2-(t-butyloxycarbonylamino)-(2-triphenylmethylamino-4-thiazolyl)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To a solution of2-(t-buthyloxycarbonylamino)-2-(2-triphenylmethylamino-4-thiazolyl)aceticacid (6.83 g) in dimethylformamide (20 ml) was added a solution of(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylicacid diphenylmethyl ester (10 g) in dichloromethane (200 ml).Dicyclohexylcarbodiimide (2.73 g) was added to the solution under icecooling and the mixture was stirred at room temperature for one hour.The insoluble matters were filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was redissolved inethyl acetate and the insoluble matters were removed by filtration. Thefiltrate was washed with brine and dried over anhydrous sodium sulfate.The dried solution was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography, giving 10.8 gof the objective compound.

MNR (DMSO-d₆, δ): 8.5 (1H, m), 8.3 (1H, m), 7.5-7.1 (37H, m), 7.0 (1H,s), 6.4 (1H, s), 5.8 (1H, m), 5.2 (1H, d, J=5 Hz), 5.0 (1H, m), 4.3 (2H,brs), 3.7 (2H, ABq), 2.6 (3H, s), 1.4 (9H, s),

Step 2:

Preparation of(6R,7R)-7-[2-amino-2-(2-triphenylmethylamino-4-thiazolyl)acetamido]-3[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the product obtained in Step 1 (1 g) in drydichloromethane was added 3 ml of methanol saturated with hydrogenchloride, and the mixture was stirred for 15 minutes. The resultingsolution was poured into saturated aqueous sodium bicarbonate solution,and extracted with dichloromethane. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, giving 0.8 g of the objective compound.

IR (KBr, cm⁻¹): 1787, 1737, 1596, 1507, 1498, 1222, 1202, 1183, 755,700,

NMR (DMSO-d₆, δ): 8.5 (1H, m), 7.5-7.2 (37H, m), 7.0 (1H, s), 6.4 (1H,s), 5.9-5.1 (3H, m), 4.3 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s),

Step 3:

Preparation of(6R,7R)-7-[2-(3,4-diacetoxybenzoylamino)-2-(2-triphenylmethylamino-4-thiazolyl)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl[-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To a solution of the product obtained in Step 2 (0.75 g) in drydichloromethane (10 ml) was added bis(trimethylsilyl)acetamide (0.32 ml)and the mixture was stirred for 30 minutes. Then a solution of3,4-diacetoxybenzoyl chloride (0.17 g) in dry dichloromethane (5 ml) wasadded dropwise at -10° C. The resulting solution was stirred for onehour and concentrated under reduced pressure. The residue was dissolvedin ethyl acetate (120 ml), and the solution was washed twice with brineand dried over anhydrous sodium sulfate. The dried solution wasconcentrated under reduced pressure, giving 0.7 g of the objectivecompound as pale yellow crystals.

IR (KBr, cm⁻¹): 1780, 1741, 1508, 1497, 1372, 1205, 1182, 700,

NMR (DMSO-d₆, δ): 9.0 (1H, d, J=7 Hz), 8.5 (1H, s), 8.2-7.1 (40H, m),6.9 (1H, s), 6.5 (1H, s), 5.8-5.1 (3H, m), 4.3 (2H, brs), 3.7 (2H, ABq),2.6 (3H, s), 2.3 (6H, s),

Step 4:

Preparation of(6R,7R)-7-[2-(2amino-4-thiazolyl)-2-(3,4-diacetoxybenzoylamino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the product obtained in Step 3 (0.65 g) indichloroethane (2 ml) were added anisole (0.5 ml) and trifluoroaceticacid (1 ml) under ice cooling, and the resulting solution was stirred atroom temperature for 2 hours. The solvent was removed by decantation,and the residue was washed with a small amount of dichloroethane andcrystallized with ether, giving 0.31 g of the objective compound as paleyellow crystals (as trifluoroacetic acid salt).

IR (KBr, cm⁻¹): 1774, 1654, 1647, 1509, 1205,

NMR (DMSO-d₆, δ): 9.2 (1H, d), 8.9-8.8 (1H, m), 7.9-7.3 (4H, m), 6.6(1H, s), 5.8-5.6 (2H, m), 5.1 (1H, d, J=4 Hz), 4.4 (2H, brs), 3.7 (2H,ABq), 2.6 (3H, s), 2.3 (6H, s),

Step 5:

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(3,4-dihydroxybenzoylamino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 4 (0.28 g) was suspended in water (10 ml),and the pH of the mixture was adjusted to 8 with sodium bicarbonate. Themixture was stirred at room temperature for 3 hours, and the resultingsolution was applied to a Diaion HP 10 column. The objective fractionseluted by 17% methanol in water were collected, concentrated to onethird of its original volume under reduced pressure, then lyophilized,giving 0.16 g of the objective compound (as sodium salt).

IR (KBr, cm⁻¹): 1763, 1624, 1599, 1514, 1406, 1352, 1314,

NMR (DMSO-d₆, δ): 9.0 (1H, m), 8.l (1H, m), 7.6 (1H, s), 7.3-6.7 (3H,m), 6.4 (1H, s), 5.7-5.5 (2H, m), 5.1-4.9 (1H, m), 4.6 (2H, ABq), 3.6(2H, ABq), 2.5 (3H, s),

Table 5 lists structures of Compounds 19 to 91 together with theirspectral data. All of these compounds have been prepared by the methodsdescribed in Examples 1 to 18. These methods can be divided into fivegroups according to the similarities in reaction procedures. Table 4shown below gives the groups of examples, and compounds which have beenprepared by the method employed by these groups of examples.

                  TABLE 4                                                         ______________________________________                                        Group      Example  Compound                                                  ______________________________________                                        1          2, 4     19-33, 35-44, 46, 48, 51-54                               2          1, 3, 5  34, 45, 47, 49, 50, 55                                    3          6, 8     56-66, 68, 70-72                                          4          7, 9-17  67, 69, 73-89                                             5          18       90, 91                                                    ______________________________________                                    

    TABLE 5      ##STR21##                   No.Example X Y R.sup.2 R.sup.3 R.sup.4 R.sup.5 a b c      ##STR22##      IR (cm.sup.-1) NMR (δ)                    19(CF.sub.3      COOHsalt)     ##STR23##      ##STR24##      O -- -- 1 1 0 doublebond 1760, 1605, 1604,1597, 1240, 1196. (DMSO-d.sub.     6); 10.0 (1H, d, J = 0 Hz),7.9-7.2 (5H, m), 7.1 (1H, m),5.9 (1H, dd, J =     5, 8 Hz), 5.3(1H, d, J = 5 Hz), 4.4 (2H, brs),3.6 (2H, ABq) 2.6 (3H, s),     2.3 (3H, s)  20(CF.sub.3      COOHsalt)     ##STR25##      ##STR26##      O -- -- 1 1 0 doublebond 1772, 1763, 1735,1604, 1640, 1596,1509, 1260,     1203. (DMSO-d.sub.6); 10.0 (1H, d, J = 7 Hz),7.7-7.3 (5H, m), 7.1 (1H,     m),5.9 (1H, dd, J = 5, 7 Hz), 5.2(1H, d, J = 5 Hz),4.4 (2H, brs),3.7     (2H, ABq), 2.6 (3H, s), 2.3 (3H, s)  21(CF.sub.3      COOHsalt)     ##STR27##      ##STR28##      O -- -- 1 1 0 doublebond 1773, 1757, 1752,1736, 1600, 1509,1250, 1199,     1164. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),8.1 (2H, d), 7.4 (1H,     s),7.3 (2H, d), 7.1 (1H, s), 6.0 (1H, dd, J = 5, 8 Hz), 5.3 (1H, d,J = 5     Hz), 4.5 (2H, brs),3.7 (2H, ABq), 2.6 (3H, s), 2.3 (3H, s)  22(CF.sub.3     COOHsalt)      ##STR29##      ##STR30##      O -- -- 1 1 0 doublebond 1770, 1604, 1637,1597, 1527, 1523,1509, 1250.     (DMSO-d.sub.6); 10.1 (1H, d, J =8 Hz),0.4-8.2 (4H, m), 7.4 (1H, m),7.2     (1H, s), 6.0 (1H, dd, J = 5,8 Hz), 5.3 (1H, d, J = 5 Hz), 4.4(2H, brs),     3.7 (2H, ABq), 2.6 (3H, s)  23(CF.sub.3      COOHsalt)     ##STR31##      ##STR32##      O -- -- 1 1 0 doublebond 1772, 1764, 1735,1685, 1637, 1597,1509, 1299,     1249. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),8.3-8.0 (4H, m), 7.4 (1H,     m),7.2 (1H, s), 6.0 (1H, dd, J = 5,8 Hz), 5.3 (1H, d, J = 5 Hz),4.5 (2H,     brs), 3.7 (2H, ABq),3.3 (3H, s), 2.6 (3H, s)  24(CF.sub.3 COOHsalt)      ##STR33##      ##STR34##      O -- -- 1 1 0 doublebond 1780, 1684, 1597,1509, 1228, 1191. (DMSO-d.sub.     6); 10.0 (1H, d, J = 9 Hz),9.6 (1H, s), 9.5 (1H, s),8.1-7.8 (3H, m), 7.4     (1H, s), 7.1(1H, s), 6.0 (1H, dd, J = 5, 9 Hz), 5.3(1H, d, J = 5 Hz),    (     4.52H, brs), 3.7 (2H, ABq), 2.6 (3H, s),2.1 (3H, s), 2.0 (3H, s)     25(CF.sub.3      COOHsalt)     ##STR35##      ##STR36##      O -- -- 1 1 0 doublebond 1773, 1764, 1684,1637, 1596, 1509,1268, 1233.     (DMSO-d.sub.6); 10.2 (1H, d, J = 8 Hz),8.1-7.8 (3H, m), 7.4 (1H, s),7.2     (1H, s), 6.0 (1H, dd, J = 5,8 Hz), 5.3 (1H, d, J = 5 Hz),4.5 (2H, brs),     3.7 (2H, ABq), 2.6 (3H, s)  26(CF.sub.3      COOHsalt)     ##STR37##      ##STR38##      O -- -- 1 1 0 doublebond 1780, 1774, 1739,1735, 1597, 1509,1260, 1246,     1201. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.6-7.1 (5H, m), 6.0 (3H,     dd, J = 5,8 Hz), 5.3 (1H, d, J = 5Hz), 4.6 (2H, brs), 4.22 (2H, qJ = 5     Hz), 4.18 (2H, q,J = 5 Hz), 3.8 (2H, ABq),2.6 (3H, s), 1.34 (3H, t,J = 5     Hz), 1.32 (3H, t, J = 5 Hz)  27(CF.sub.3      COOHsalt)     ##STR39##      ##STR40##      O -- -- 1 1 0 doublebond 1774, 1637, 1610,1596, 1509, 1293. (DMSO-d.sub.     6); 10.1 (1H, d, J = 8 Hz),7.7-7.3 (4H, m), 7.1 (1H, s),6.0 (1H, dd, J =     5, 8 Hz), 5.2(1H, d, J = 5 Hz), 4.5 (2H, brs),4.3 (4H, s), 3.8 (2H,     ABq), 2.6 (3H, s)  28(CF.sub.3      COOHsalt)     ##STR41##      ##STR42##      O -- -- 1 1 0 doublebond 1771, 1686, 1638,1596, 1511, 1371,1256, 1178,     1099. (DMSO-d.sub.6); 10.1 (1H, d, J = 7 Hz),8.1-7.7 (3H, m), 7.4 (1H,     s),7.2 (1H, s), 6.0 (1H, dd, J = 5,7 Hz), 5.3 (1H, d, J = 5 Hz),4.4 (2H,     brs), 3.7 (2H, ABq,3.6 (3H, s), 3.5 (3H, s), 2.6 (3H, s)  29(CF.sub.3     COOHsalt)      ##STR43##      ##STR44##      O -- -- 1 1 0 doublebond 1771, 1764, 1736,1597, 1509, 1279,1260, 1170,     1111. (DMSO-d.sub.6); 10.2 (1H, d, J = 8 Hz),8.1-7.1 (5H, m), 5.9 (1H,     dd, J = 5, 8 Hz), 5.3 (1H, d, J = 5Hz), 4.5 (2H, brs), 3.7 (2H, ABq),2.6     (11H, brs 1.1 (6H, t, J = 7 Hz)  30(CF.sub.3      COOHsalt)     ##STR45##      ##STR46##      O -- -- 1 1 0 doublebond 1764, 1737, 1690,1642, 1598, 1509,1206, 1219,     1197,1168. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.7 (1H, d, J = 8     Hz),7.6 (1H, s) 7.4 (1H, s), 7.2 (1H, d, J= 8 Hz), 7.1 (1H, s), 5.9 (1H,     dd, J = 5,8 Hz), 5.2 (1H, d, J = 5 Hz), 4.4(2H, brs), 3.9 (3H, s), 3.7     (2H, ABq),2.6 (3H, s), 2.3 (3H, s)  31(CF.sub.3      COOHsalt)     ##STR47##      ##STR48##      O -- -- 1 1 0 doublebond 1779, 1685, 1637,1596, 1508, 1279,1260, 1169,     1118. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),8.1-7.1 (5H, m), 5.9     (1H,dd, J = 5, 8 Hz), 5.3 (1H, d,J = 5 Hz), 4.8 (2H, s),4.7 (2H, s), 4.5     (2H, brs), 3.7(2H, ABq), 2.6 (3H, s),  32(CF.sub.3      COOHsalt)     ##STR49##      ##STR50##      O -- -- 1 1 0 doublebond 1773, 1763, 1752,1686, 1637, 1509,1200.     (DMSO-d.sub.6); 10.0 (1H, d, J = 8 Hz),8.0 (1H, d, J = 9 Hz),7.4-7.1     (4H, m), 5.9 (1H, dd, J = 5, 8Hz), 5.2 (1H, d, J = 5 Hz),4.4 (2H, brs),     3.7 (2H, ABq),2.6 (3H, s) 2.3 (3H, s)  33(CF.sub.3      COOHsalt)     ##STR51##      ##STR52##      O -- -- 1 1 0 doublebond 1839, 1773, 1735,1605, 1637, 1597,1509, 1269,     1249, 1106. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz), 3.3-7.6 (3H, m),7.4     (1H, s), 7.2 (1H, s),6.1 (1H, dd, J = 5, 8 Hz), 5.3 (1H, d, J =5 Hz),     4.4 (2H, brs), 3.8 (2H, ABq),2.6 (3H, s),      34     ##STR53##      ##STR54##      O -- -- 1 1 0 doublebond 1773, 1735, 1654,1598, 1509, 1298. (DMSO-d.sub.     6); 10.1 (1H, d, J = 8 Hz),7.4-6.8 (5H, m), 5.9 (1H, dd, J = 5,8 Hz),     5.3 (1H, d, J = 5Hz), 4.5 (2H, brs), 3.7 (2H, ABq),2.6 (3H, s)      35(CF.sub.3      COOHsalt)     ##STR55##      ##STR56##      O -- -- 1 1 0 doublebond 1780, 1685, 1637,1597, 1945, 1509,1292, 1192,     1143. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),8.8 (1H, d, J = 2 Hz),8.4     (1H, d, J = 2 Hz), 7.4 (1H, s),7.2 (1H, s), 6.0 (1H, dd, J = 5,8 Hz),     5.3 (1H, d, J = 5 Hz),4.5 (2H, brs), 3.7 (2H, ABq),2.6 (3H, s), 2.4 (3H,     s), 2.3 (3H, s)  36(CF.sub.3      COOHsalt)     ##STR57##      ##STR58##      O -- -- 1 1 0 doublebond 1775, 1686, 1638,1597, 1510, 1205,1158.     (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.8 (1H, s), 7.7 (1H, s),7.4 (1H,     s), 7.1 (1H, s), 6.0 (1H,dd, J = 5, 8 Hz), 5.3 (1H, d, J = 5 Hz),4.5     (2H, brs), 3.7 (2H, ABq),2.6 (3H, s), 24. (3H, s), 2.3 (3H, s)2.2 (3H,     s)  37(CF.sub.3      COOHsalt)     ##STR59##      ##STR60##      O -- -- 1 1 0 doublebond  1772, 1685, 15981509, 1251, 1203,1165.     (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.8 (1H, d, J = 9 Hz),7.4 (1H,     s), 7.3 (1H, d, J = 9 Hz),7.1 (1H, s), 5.8 (1H, dd, J = 5, 8 Hz),5.2     (1H, d, J = 5 Hz),4.4 (2H, brs), 3.6 (2H, ABq), 2.6 (3H s) 2.34 (3H, s),     2.33 (3H, s),2.27 (3H, s)  38(CF.sub.3      COOHsalt)     ##STR61##      ##STR62##      O -- -- 1 1 0 doublebond 1781, 1637, 1597,1509, 1324, 1234,1170, 1128.     (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),8.0 (2H, s),7.4 (1H, s),7.2 (1H,     s), 5.9 (1H, dd, J = 5,8 Hz), 5.3 (1H, d, J = 5 Hz),4.8 (2H, s), 4.7     (4H, s),4.5 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s),  39(CF.sub.3      COOHsalt)      ##STR63##      ##STR64##      O -- -- 1 1 0 doublebond 1774, 1685, 1637,1598, 1509, 1340,1196, 1164,     1097. (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.5 (2H, s), 7.4 (1H,     s),7.1 (1H, s), 5.9 (1H, dd, J = 5, 8Hz), 5.2 (1H, d, J = 5 Hz), 4.5     (2H, brs),3.9 (3H, s), 3.7 (2H, ABq),2.6 (3H, s), 2.31 (3H, s), 2.27     (3H, s)  40(CF.sub.3      COOHsalt)     ##STR65##      ##STR66##      O -- -- 1 1 0 doublebond 1781, 1685, 1637,1597, 1509, 1260,1181.     (DMSO-d.sub.6); 10.1 (1H, d, J = 7 Hz),7.9 (1H, d, J = 9 Hz),7.4 (1H,     s), 7.2 (1H, d, J = 9 Hz),7.1 (1H, s), 5.9 (1H, dd, J = 5, 7 Hz),5.2     (1H, d, J = 5 Hz),4.4 (2H, brs), 3.7 (2H, ABq), 2.6(3H, s), 2.3 (9H, s)  4     1(CF.sub.3      COOHsalt)     ##STR67##      ##STR68##      O -- -- 1 1 0 doublebond 1774, 1685, 1676,1654, 1590, 1509,1199, 1162,     1124. (DMSO-d.sub.6); 10.0 (1H, d, J = 8 Hz),7.8 (1H, s), 7.42 (1H,     s),7.37 (1H, s), 7.1 (1H, s), 5.9 (1H,dd, J = 5, 8 Hz), 5.2 (1H, d, J =     5 Hz),4.5 (2H, brs). 3.7 (2H, ABq),2.6 (3H, s), 2.30 (6H, s) 2.27 (3H,     s) 42(CF.sub.3      COOHsalt)     ##STR69##      ##STR70##      O -- -- 1 1 0 doublebond 1781, 1685, 1597,1509, 1201, 1182,1125.     (DMSO-d.sub.6); 10.1 (1H, d, J = 9 Hz),7.8 (1H, s), 7.4 (2H, s), 7.1     (1H, s),5.9 (1H, dd, J = 5, 9 Hz),5.2 (1H, d, J = 5 Hz), 4.7 (2H, s),4.6     (2H, s), 4.5 (2H, brs),3.7 (2H, ABq), 2.6 (3H, s), 2.5 (3H, s),     43(CF.sub.3      COOHsalt)     ##STR71##      ##STR72##      O -- -- 1 1 0 doublebond 1773, 1597, 1508,1203, 1180. (DMSO-d.sub.6);     10.0 (1H, d, J = 7 Hz),7.6 (1H, s), 7.4 (1H, s), 7.2 (1H, s), 7.1 (1H,     s), 5.8 (1H,dd, J = 4, 7 Hz), 5.2 (1H, d, J = 4 Hz),4.4 (2H, brs), 3.8     (3H, s),3.7 (2H, ABq), 2.6 (3H, s)2.26 (3H, s) 2.22 (3H, s)  44(CF.sub.3     COOHsalt)      ##STR73##      ##STR74##      O -- -- 1 1 0 doublebond 1779, 1683, 1635,1590, 1510, 1243,1209, 1117.     (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.9 (1H, d, J = 9 Hz), 7.41 (1H,     s), 7.36 (1H, d,J = 9 Hz), 7.2 (1H, s),5.9 (1H, dd, J = 5, 8 Hz),5.2     (1H, d, J = 5 Hz),4.9 (2H, s), 4.7 (2H, s),4.4 (2H, brs), 3.6 (2H,     ABq),2.6 (3H, s) 2.4 (3H, s),      45     ##STR75##      ##STR76##      O -- -- 1 1 0 doublebond 1778, 1773, 1735,1637, 1597, 1509,1302, 1245.     (DMSO-d.sub.6); 10.1 (1H, d, J = 8 Hz),7.42 (1H, s), 7.37 (1H, d,J = 10     Hz), 7.1 (1H, s),6.8 (1H, d J = 10 Hz), 5.9 (1H, dd,J = 5, 8 Hz), 5.2     (1H, d),J = 5 Hz), 4.5 (2H, brs), 3.7 (2H, ABq),2.6 (3H, s), 2.4 (3H, s)      46(CF.sub.3      COOHsalt)     ##STR77##      ##STR78##      O -- -- 1 1 0 doublebond 1772, 1764, 1735,1636, 1597, 1509,1239, 1203.     (DMSO-d.sub.6 ); 10.1 (1H, d, J = 9 Hz),8.7 (1H, s), 8.1 (1H, s),8.0     (1H, s), 7.4 (1H, s),7.1 (1H, s), 6.0 (1H, dd,J = 5, 9 Hz), 5.3 (1H, d,J     = 5 Hz), 4.4 (2H, brs),3.7 (2H, ABq), 2.6 (3H, s), 2.4 (6H, s),  47      ##STR79##      ##STR80##      O -- -- 1 1 0 doublebond 1774, 1763, 1719,1654, 1597, 1509,1220, 1165,     1133. (DMSO-d.sub.6); 10.1 (1H, d, J = 9 Hz),8.7 (1H, m), 8.2 (2H,     m),7.8 (2H, m), 7.4 (1H, s),7.2 (1H, s), 5.9 (1H, dd,J =  5, 9 Hz), 5.2     (1H, d,J = 5 Hz), 4.4 (2H, brs),3.6 (2H, ABq), 2.6 (3 s)  48(3H,     (CF.sub.3      COOHsalt)     ##STR81##      ##STR82##      O -- -- 1 1 0 doublebond 1773, 1595, 1508. (DMSO-d.sub.6); 10.1 (1H, d,     J = 9 Hz),7.7 (1H, s), 7.5 (1H, s),7.4 (1H, s), 7.1 (1H, s),5.8 (1H, dd,     J = 5, 9 Hz),5.2 (1H, d, J = 5 Hz), 4.7 (2H,s), 4.6 (2H, s), 4.4 (2H,    3     s),.6 (2H, brs), 3.5(1H, m),2.6 (3H, s), 1.2-1.0 (6H, s)      49     ##STR83##      ##STR84##      O -- -- 1 1 0 doublebond 1773, 1741, 1654,1630, 1597, 1515,1509.     (DMSO-d.sub.6); 10.0 (1H, d, J = 9 Hz),7.4 (1H, s), 7.2 (1H, s),7.1 (1H,     s), 6.8 (1H, s), 5.9 (1H,dd, J = 5, 9 Hz), 5.2 (1H, d, J = 5 Hz),4.4     (2H, brs),3.7 (1H, m), 2.6 (3H, s),1.1 (6H, d, J = 7 Hz)      50     ##STR85##      ##STR86##      O -- -- 1 1 0 doublebond 1772, 1764, 1753,1637, 1597, 1512,1200.     (DMSO-d.sub.6); 10.0 (1H, d, J = 9 Hz),7.4 (1H, s), 7.3 (1H, s),7.1 (3H,     s), 6.9 (1H, s),5.8 (1H, dd, J = 5, 9 Hz),5.2 (1H, d, J = 5 Hz),4.4 (2H,     brs), 3.6 (2H, ABq),2.6 (3H, s)  51(CF.sub.3      COOHsalt)     ##STR87##      ##STR88##      O -- -- 1 1 0 doublebond 1778, 1774, 1764,1736, 1509, 1204,1141.     (DMSO-d.sub.6); 10.1 (3H, d, J = 8 Hz),7.6 (1H, s), 7.42 (1H, s),7.39     (1H, s), 7.1 (1H, s),5.9 (1H, dd, J = 5, 8 Hz),5.2 (1H, d, J = 5 Hz),     4.4 (2H,brs), 3.7 (2H, ABq), 3.6 (1H, m),2.6 (3H, s), 2.26 (3Hz s),2.24     (3H, s), 1.2 (3H, d,J = 5 Hz), 1.1 (3H, d,J = 5 Hz)  52(CF.sub.3     COOHsalt)      ##STR89##      ##STR90##       O -- -- 1 1 0 doublebond 1775, 1676, 1637,1597, 1509, 1374,1316, 1199,     1144. (DMSO-d.sub.6); 10.1 (1H, d, J = 9 Hz),7.7 (1H, s), 7.4 (1H,     s),7.1 (3H, s), 5.8 (1H, dd,J = 5, 9 Hz), 5.2 (1H, d,J = 5 Hz), 4.4 (2H,     brs), 3.7(2H, ABq), 2.6 (3H, s), 2.4(3H, s), 2.3 (6H, s) 2.2 (3H, s)     53(CF.sub.3      COOHsalt)     ##STR91##      ##STR92##      O -- -- 1 1 0 doublebond 1775, 1735, 1676,1634, 1599, 1508,1262, 1202.     (DMSO-d.sub.6); 10.0 (1H, d, J = 8 Hz),7.6-6.7 (5H, m), 6.0 (1H, dd,J =     5, 8 Hz), 5.3 (1H, d, J = 5Hz), 4.4 (2H, brs), 3.7 (2H, ABq),2.6 (3H, s)      54(CF.sub.3      COOHsalt)     ##STR93##      ##STR94##      O -- -- 1 1 0 doublebond 1780, 1773, 1730,1617, 1597, 1509,1219, 1199.     (DMSO-d.sub.6); 10.2 (1H, d, J = 8 Hz),9.3 (1H, s), 9.2 (1H, s),8.3-7.1     (15H, m), 5.9 (1H,dd, J = 5, 8 Hz), 5.3 (1H, d, J = 5 Hz),5.2 (4H, s),     4.4 (2H, brs), 3.7 (2H, ABq), 2.6 (3H, s)      55     ##STR95##      ##STR96##      O -- -- 1 1 0 doublebond 1773, 1654, 1595,1509, 1369. (DMSO-d.sub.6);     10.0 (1H, d, J = 8 Hz),7.4 (1H, s), 7.3 (1H, s),7.1 (1H, s), 6.7 (1H,     s), 5.9(1H, dd, J = 5, 8 Hz),5.2 (1H, d, J = 5 Hz),4.4 (2H, brs), 3.6     (2H, ABq),2.6 (3H, s), 2.4 (3H, s)               56(CF.sub.3 COOHsalt) H      ##STR97##      -- -- -- -- 1 0 0 doublebond 1773, 1695, 1647,1500, 1542. (DMSO-d.sub.6)     ; 11.9 (1H, s), 9.6 (1H, d,J = 9 Hz), 8.6 (1H, s),6.8 (1H, s), 5.8 (1H,     dd,J = 5, 9 Hz), 5.2 (1H, d,J = 5 Hz), 4.3 (2H, ABq),3.7 (2H, ABq)     57(CF.sub.3      COOHsalt) H     ##STR98##      -- -- -- -- 1 0 0 doublebond 1774, 1684, 1630,1541, 1370, 1187.     (DMSO-d.sub.6); 11.3 (3H, s),9.4 (1H, d, J = 8 Hz), 8.5(1H, s), 7.5 (3H,     s), 6.6 (1H, s),5.8 (1H, dd, J = 5, 8 Hz),5.1 (1H, d, J = 5 Hz),4.4 (2H,     ABq), 3.7 (2H, ABq)              58(CF.sub.3      COOHsalt) OH     ##STR99##      H H O 1 1 1 doublebond 1775, 1595, 1515,1355, 1255, 1195,1000. (DHSO-d.s     ub.6); 9.5 (1H, d, J = 9 Hz),8.6 (1H, s), 7.3 (1H, s), 6.8 (1H, s),5.8     (1H, dd, J = 5, 9 Hz), 3.7 (2H, ABq),2.6 (3H, s)  59(CF.sub.3 COOHsalt)     OH      ##STR100##      H H O 1 1 1 doublebond 1774, 1630, 1595,1505, 1400, 1240. (DMSO-d.sub.6)     ; 9.5 (1H, d, J = 9 Hz),7.4 (1H, s), 6.8 (1H, s),5.8 (1H, dd, J = 5, 9     Hz),5.2 (1H, d, J = 5 Hz),4.6 (2H, s), 4.4 (2H, s),3.7 (2H, ABq), 2.6     (3H, s)  60(CF.sub.3      COOHsalt) OH     ##STR101##      CH.sub.3 CH.sub.3 O 1 1 1 doublebond 1775, 1675, 1630,1595, 1515,     1360,1190. (DMSO-d.sub.6); 9.5 (1H, d, J = 9 Hz),8.6 (1H, s), 7.3 (1H,     s),6.7 (1H, s), 5.8 (1H, dd,J = 5, 9 Hz), 5.2 (3H, d, J = 5 Hz),4.4 (2H,     s), 3.7 (2H, ABq),2.6 (3H, s), 1.4 (6H, s)                61(CF.sub.3     COOHsalt)      ##STR102##      ##STR103##      H H -- -- 1 1 0 doublebond 1780, 1683, 1637,1599, 1509, 1198. (DMSO-d.su     b.6); 9.8 (1H, d, J = 8 Hz),7.4-6.7 (5H, m),5.8 (1H, dd, J = 5, 8 Hz),     5.2 (1H,d, J = 5 Hz), 4.9 (2H, brs),4.4 (2H, brs), 3.7 (2H, ABq), 2.6     (3H, s)              62(CF.sub.3      COOHsalt)     ##STR104##      ##STR105##      H H O 1 1 1 doublebond 1774, 1685, 1596,1509, 1202. (DMSO-d.sub.6); 9.8     (1H, d, J = 8 Hz),8.0-7.4 (4H, m) 6.8(1H, s), 5.9 (1H, dd, J = 5,8 Hz),     5.4 (2H, s), 5.2 (1H,d, J = 5 Hz), 4.4 (2H, brs), 3.6 (2H,ABq), 2.6 (3H,     s), 2.3 (6H, s)  63(CF.sub.3      COOHsalt)     ##STR106##      ##STR107##      CH.sub.3 CH.sub.3 O 1 1 1 doublebond 1774, 1683, 1597,1512. (DMSO-d.sub.     6 ); 9.9 (1H, d, J = 8 Hz),8.7 (1H, s), 7.4 (1H, s),7.1-6.6 (4H, m), 5.9     (1H,dd, J = 5, 8 Hz), 5.3 (1H,d, J = 5 Hz), 4.4 (2H, brs)3.7 (2H, ABq),     2.6 (3H, s),1.5 (6H, s)               64(CF.sub.3      COOHsalt)     ##STR108##      ##STR109##      -- -- -- -- 1 0 0 doublebond 1784, 1605, 1676,1637, 1598, 1509,1491,     1375, 1195,1180. (DMSO-d.sub.6); 9.9 (1H, d, J = 8 Hz),7.6-7.0 (13H,     m),5.9 (1H, dd, J = 5, 8 Hz), 5.3 (1H,d, J = 5 Hz), 4.4 (2H, brs),3.7     (2H, s), 2.6 (3H, s), 2.41 (3H, s) 2.38 (3H, s)              65(CF.sub.3     COOHsalt)      ##STR110##      ##STR111##      CH.sub.3 CH.sub.3 O 1 1 1 doublebond 1781, 1774, 1676,1671, 1637,     1196,1143. (DMSO-d.sub.6); 9.6 and 9.5 (1H, m),7.4 (1H, s), 7.2 (3H,     s),6.84 and 6.81 (1H, s), 5.8 (1H, m),5.2 (1H, d, J = 4 Hz),4.8 (1H, m),     4.4 (2H, brs),3.7 (2H, ABq), 3.2 (2H, m),2.6 (3H, s), 2.2 (6H, s)            66(CF.sub.3      COOHsalt)     ##STR112##      ##STR113##      H COOH H H 1 1 1 doublebond 1772, 1735, 1684,1637, 1597, 1509,1259,     1205, 1189. (DMSO-d.sub.6); 9.6 (1H, d, J = 8 Hz)8.0 (1H, s), 7.4 (2H,   6     s).8 (1H, s), 5.9 (1H, dd,J = 4, 8 Hz), 5.3 (1H, d,J = 4 Hz), 4.4 (2H,     brs),3.7 (2H, ABq), 2.6 (3H, s),2.3 (3H,s), 1.6 (6H, s)  67(Na salt)      ##STR114##      ##STR115##      H COOH H H 1 1 1 doublebond 1765, 1597, 1516,1474, 1408, 1356,1314.     (D.sub.2 O); 7.4 and 7.2 (1H, s), 7.0 (1H, s),6.8-6.6 (3H, s), 5.7 (1H,     m),5.2 (1H, m), 5.0 (1H, m),4.5 (2H, ABq), 3.7 (2H, ABq), 3.0 (2H,m),     2.6 (3H, s)  68(CF.sub.3      COONsalt)     ##STR116##      ##STR117##      H H -- -- 1 1 0 doublebond 1772, 1741, 1654. (DMSO-d.sub.6); 9.4 (1H,     d, J = 8 Hz),7.4 (1H, s), 7.3 (1H, s), 7.0 (3H, s),6.8 (1H, s), 5.8 (1H,     dd,J = 4, 8 Hz), 5.7 (1H, s),5.1 (1H, d, J = 4 Hz),4.4 (2H, brs), 3.6     (2H, ABq),2.6 (3H, s), 2.4 (3H, s), 2.2 (6H, s)      69(Na salt)     ##STR118##      ##STR119##      H COOH -- -- 1 1 0 doublebond 1770, 1597, 1513,1407, 1384, 1311.     (D.sub.2      O); 7.3-6.6 (4H, m), 5.63-5.59(2H, m), 5.01-4.95 (1H, m),4.8-4.4 (2H,     m), 3.6-3.0 (2H, m),2.6 (3H, s), 2.23 and 2.17 (3H, s)  70(CF.sub.3     COOHsalt)      ##STR120##      ##STR121##      H COOH -- -- 1 1 0 doublebond 1774, 1676, 1637,1597, 1511, 1190.     (DMSO-d.sub.6), 9.5 (1H, m), 7.4 (3H, m),6.84 and 6.81 (1H, s),6.7 (3H,     m), 5.96 and 5.91 (1H, s),5.8 (1H, m), 5.2 (1H, d, J = 5 Hz),4.4 (2H,     brs), 3.7 (2H, ABq, 2.6 (3H, s)  71(CF.sub.3      COOHsalt)     ##STR122##      ##STR123##      H COOH -- -- 1 1 0 doublebond 1778, 1722, 1675,1636, 1597, 1509,1200.     (DMSO-d.sub.6); 9.5 (1H, m), 7.5-7.0(6H, m), 6.83 and 6.80(1H, s), 5.9     (1H, m), 5.6 (1H, s),5.2 (1H, m), 4.4 (2H, brs),3.7 (2H, ABq), 2.6 (3H,     s)  72(CF.sub.3      COOHsalt)     ##STR124##      ##STR125##      H COOH -- -- 1 1 0 doublebond 1773, 1735, 1675,1509, 1202. (DMSO-d.sub.6     ); 7.6-7.1(5H, m), 6.83 and 6.79 (1H, s),5.6 (1H, m), 5.6 (1H, s),5.1     (1H, m), 4.4 (2H, trs),3.6 (2H, ABq), 2.6 (3H, s),2.25 and 2.20 (3H, s)  7     3(Na salt)      ##STR126##      ##STR127##      H COOH -- -- 1 1 0 doublebond 1762, 1654, 1616, 1598, 1406. (D.sub.2     O); 7.5-6.8 (6H, m), 5.7 (1H, m),5.5 (1H, s), 5.0 (1H, m), 4.4 (2H,      3     ABq),.4 (2H, ABq), 2.6 (3H, s)      74(Na salt)     ##STR128##      OCOCH.sub.3 H COOH -- -- 1 1 0 doublebond 1772, 1762, 1751,1617, 1399     (D.sub.2 O); 7.0-6.9 (4H, m), 5.8 (1H, m)5.4 (1H, s), 3.4 (2H, ABq), 2.1     (3H, s)      75(Na salt)     ##STR129##      ##STR130##      H COOH -- -- 1 1 0 doublebond 1773, 1597, 1529,1390, 1358. (D.sub.2 O);     8.7 (1H, s), 7.0-6.8 (4H, m),5.7 (1H, m), 5.4 (1H, s), 5.0 (1H, s),4.3     (2H, ABq), 3.3 (2H, ABq)      76(Na salt)     ##STR131##      ##STR132##      H COOH -- -- 1 1 0 doublebond 1763, 1596, 1509,1397, 1368. (D.sub.2 O);     7.2 (1H, s), 7.0-6.9 (4H, m),5.7 (1H, m), 5.4 (1H, s), (1H, s), 5.0 (1H,     m),4.3 (2H, ABq), 3.4 (2H, ABq), 2.6 (3H, s)      77(Na salt)     ##STR133##      ##STR134##      H COOH -- -- 1 1 0 doublebond 1763, 1596, 1513,1399, 1205. (D.sub.2 O);     8.5 and 8.3 (1H, s), 7.2 -6.8(5H, m), 5.6 (1H, m), 5.4 (1H, s),5.0 (1H,     m), 3.4 (2H, ABq),2.6 and 2.4 (2H, s)      78(Na salt)     ##STR135##      ##STR136##      H COOH -- -- 1 1 0 doublebond 1763, 1612, 1533,1475, 1396. (D.sub.2);     8.4 (1H, s), 7.3 (1H, s),7.0-6.9 (4H, m),5.7 (1H, m), 5.4 (1H, s),5.0     (1H, m), 4.3 (2H, ABq), 3.4 (2H, ABq),2.6 (3H, s)      79(Na salt)     ##STR137##      ##STR138##      H COOH -- -- 1 1 0 doublebond 1763, 1617, 1534,1458, 1397, 1368,1318.     (D.sub.2 O); 7.4 (1H, s), 7.0-6.9 (4H, m),5.7 (1H, m), 5.4 (1H, s), 5.0     (1H, m),4.3 (2H, ABq), 3.4 (2H, ABq),2.6 (3H, s)      80(Na salt)     ##STR139##      ##STR140##      H COOH -- -- 1 1 0 doublebond 1763, 1597, 1423, 1396. (D.sub.2 O); 8.6     (1H, s), 7.0-6.8 (4H, m),5.6 (1H, m), 5.4 (1H, s), 3.4 (2H, ABq)  81(Na     salt)      ##STR141##      ##STR142##      H COOH -- -- 1 1 0 doublebond 1773, 1637, 1560,1400. (D.sub.2 O);     7.0-6.9 (4H, m), 5.6 (1H, m),5.4 (1H, s), 5.1 (1H, m), 4.0 (3H, s),3.4     (2H, ABq)      82(Na salt)     ##STR143##      ##STR144##      H COOH -- -- 1 1 0 doublebond 1772, 1610, 1508,1384. (D.sub.2 O);     7.0-6.9 (4H, m), 5.7 (1H, m),5.4 (1H, s), 5.0 (2H, s), 4.2 (2H,ABq), 3.4     (2H, ABq)      83(Na salt)     ##STR145##      ##STR146##      H COOH -- -- 1 1 0 doublebond 1765, 1597, 1531,1388. (D.sub.2 O);     7.0-6.9 (4H, m), 5.7 (1H, m),5.4 (1H, s), 5.0 (1H, m), 4.2 (2H, ABq),3.4     (2H, ABq), 2.7 (3H, s)      84(Na salt)     ##STR147##      ##STR148##      H COOH -- -- 1 1 0 doublebond 1763, 1598, 1533,1396. (D.sub.2 O);     7.0-6.9 (4H, m),6.4 (1H, s), 5.7 (1H, m), 5.4 (1H, s),5.0 (1H, m), 3.5     (2H, ABq), 2.4 (3H, s)      85(Na salt)     ##STR149##      ##STR150##      H COOH -- -- 1 1 0 doublebond 1762, 1662, 1533,1395. (D.sub.2 O); 8.5     (1H, s), 7.3 (1H, s), 7.0-6.8 (4H,m), 5.8 (1H, m), 5.4 (1H, s), 3.6 (2H,     ABq)      86(Na salt)     ##STR151##      ##STR152##      H COOH -- -- 1 1 0 doublebond 1762, 1670, 1592,1590, 1394. (D.sub.2 O);     7.0-6.9 (4H, m), 5.7 (1H, m), 5.4(1H, s), 5.01 and 4.96 (1H, s)  87 (Na     salt)      ##STR153##      ##STR154##      H COOH -- -- 1 1 0 doublebond 1763, 1623, 1595,1395. (D.sub.2 O); 8.5     (1H, s), 7.2 (1H,s),7.0-6.9 (4H, m), 5.7 (1H, m),5.1 (1H, s), 5.0 (1H,     m),4.5 (2H, ABq), 3.5 (2H, ABq),2.6 (2H, s)      88(Na salt)     ##STR155##      ##STR156##      H COOH -- -- 1 1 0 doublebond 1752, 1596, 1528,1395. (D.sub.2 O);     7.0-6.9 (4H, m), 5.6 (1H, m),5.4 (1H, s), 5.0-5.1 (1H, m),3.8-3.3 (4H,     m)       89(Na salt)     ##STR157##      ##STR158##      H COOH -- -- 1 1 0 doublebond 1762, 1624, 1598,1396. (D.sub.2 O);     7.0-6.9 (4H, m), 6.2 (1H, s),5.7 (1H, m), 5.4 (1H, s),3.3 (2H, ABq)             90(CF.sub.3      COOHsalt)     ##STR159##      ##STR160##      O -- --  0 1 0 singlebond 1774, 1654, 1647,1509, 1205. (DMSO-d.sub.6);     9.2 (1H, d), 8.9-8.8(1H, m), 7.9-7.3 (4H, m), 6.6 (1H, s),5.8-5.6 (2H,     m), 5.1 (1H, d,J =      4 Hz), 4.4 (2H, brs),3.7 (2H, ABq), 2.6 (3H, s),2.3(6H, s)  91(CF.sub.3     COOHsalt)      ##STR161##      ##STR162##      O -- -- 0 1 0 singlebond 1779, 1512, 1203,1191. (DMSO-d.sub.6); 9.2     (1H, d, J = 8 Hz),8.8 (1H, d, J = 6 Hz),7.8 (2H, s), 7.4 (1H, s),6.6     (1H, s), 5.8 (1H, dd,J = 5, 8 Hz), 5.6 (1H, d,J = 6 Hz), 5.1 (1H, d,J =     5Hz), 4.4 (2H, brs),3.7 (2H, ABq) 2.6 (3H, s), 2.3 (9H, s)      ##STR163##      Example          a bond of   No. X R.sup.1 R.sup.2 R.sup.3 R.sup.4     R.sup.5 a b c      ##STR164##      IR (cm.sup.-1) NMR (δ)       92      ##STR165##      (C.sub.6 H.sub.5).sub.3 C CH.sub.3 COOCH(C.sub.5 H.sub.5).sub.2 -- -- 1     1 0 doublebond 1773, 1751, 1743,1262, 1209, 1168,1115, 701. (DMSO-d.sub.6     ); 6.8 (1H, s), 7.6-6.9 (28H, m), 6.8(1H, s), 6.7 (1H, s), 2.3 (6H, s),     1.9 (3H, s)                  93     ##STR166##      (C.sub.6 H.sub.5).sub.3 C CH.sub.3 CH.sub.3 O 1 1 1 doublebond 1685,     1600, 1598,1532, 1521, 1509,1215, 1197, 1164,1100, 702. (DMSO-d.sub.6);     8.91 (1H, s), 8.87 (1H, s), 7.6-7.0(18H, m), 6.9 (1H, s), 5.2 (4H, s),     3.6 (8H, m),3.22 (3H, s), 3.21 (3H, s), 1.5 (6H, s)               94      ##STR167##      (C.sub.6 H.sub.5).sub.3 C -- -- -- -- 1 0 0 doublebond 1598, 1491,      1     1380,195, 1180, 1168,1080, 850, 705. (DMSO-d.sub.6); 8.9 (1H, s),     7.7-6.9 (27H, m), 2.4(6H, s)      95     ##STR168##      (C.sub.6 H.sub.5).sub.3 C H COOCH(C.sub.6 H.sub.5).sub.2 H H 1 1 1     doublebond 1768, 1764, 1752,1214, 1185, 701. (DMSO-d.sub.6); 8.8 (1H,     s), 7.5-6.9 (28H, m), 6.8(2H, s), 5.0 (1H, t, J = 7 Hz), 3.2 (2H, d, J = 7      Hz), 2.2 (6H, s)      96     ##STR169##      (C.sub.6 H.sub.5).sub.3 C H COOCH(C.sub.6 H.sub.5).sub.2 -- -- 1 1 0     doublebond 1772, 1764, 1210,1181, 700. (DMSO-d.sub.6); 8.9 (1H, s),     7.4-7.0 (27H, m), 6.9(2H, s), 6.0 (1H, s), 2.3 (9H, s)      97     ##STR170##      (C.sub.6 H.sub.5).sub.3 C H COOCH(C.sub.6 H.sub.5).sub.2 -- -- 1 1 0     doublebond 1734, 1624, 1595,1491, 1478, 1285,1183, 700. (DMSO-d.sub.6);     9.6 (1H, s), 8.91 (1H, s), 8.86 (1H,s), 7.6-7.0 (27H, m), 6.8 (2H, s),     6.6 (1H, s),6.1 (1H, s)      98     ##STR171##      (C.sub.6 H.sub.5).sub.3 C H COOCH(C.sub.6 H.sub.5).sub.2 -- -- 1 1 0     doublebond 1741, 1542, 1496,1449, 1253, 1182,659. (CDCl.sub.3); 7.6-6.9     (31H, m), 6.9 (1H, s), 6.8 (1H,s), 6.0 (1H, s)      99     ##STR172##      (C.sub.6 H.sub.5).sub.3 C H COOCH(C.sub.6 H.sub.5).sub.2 -- -- 1 1 0     doublebond 1761, 1758, 1751,1745, 1540, 1533,1507, 1496, 1202,1167.     (DMSO-d.sub.6); 8.9 (1H, s), 7.5-6.9 (29H, m), 6.85(1H, s), 6.82 (1H,     s), 5.9 (1H, s), 2.3 (3H, s)

The following examples detail typical pharmaceutical preparationscontaining the cephalosporin derivatives of the present invention. Theseexamples are not intended to limit the types of compounds to be used,but the methods are applicable to all the compounds of the presentinvention.

EXAMPLE A (Method of manufacturing freeze-dried parenteral injections)

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-carboxy[(3,4-dihydroxyphenyl)methyl]imino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]phrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (1.1 g) was dissolved in 22 ml of sterile water containing anequivalent amount of sodium bicarbonate, and 2 ml each of this solutionwas poured into 5-ml ampoules, freeze-dried and sealed by ordinarymethods, to produce a freeze-dried preparation for parenteralinjections.

EXAMPLE B (Method of manufacturing tablets for oral administration)

Granules were prepared by ordinary methods using 250 mg of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-diacetoxy-2-methylbenzoyl)oxyimino)acetamido]3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-6l)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid, 100 mg of lactose, 30 mg of starch, and 10 mg of polyvinylpyrrolidone. Starch (30 mg) and magnesium stearate (5 mg) were furtheradded to the granules, and the resulting mixture was compressed intotablets, each piece weighing 425 mg.

EXAMPLE C (Method of manufacturing gelatin capsules for oraladministration)

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(4,5-dihydroxy-2-methylbenzoyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo]4.2.0]oct-2-ene-2-carboxylicacid (250 mg), water-soluble polyvinyl pyrrolidone (15 mg), mannitol (15mg), talc (15 mg) and magnesium stearate (5 mg) were uniformly mixed,and filled into gelatin capsules each weighing 300 mg.

What is claimed is:
 1. An intermediate compound in the synthesis ofcephalosporin derivatives represented by the formula (XV): ##STR173## orsalts, solvates or salts of solvates thereof, wherein R¹ represents ahydrogen atom or a amino-protecting group, R² represents a hydrogen atomor a methyl group, R³ represents a carboxyl group or a protectedcarboxyl group, R⁷ represents a hydrogen atom, a chlorine atom, acarboxyl group, a protected carboxyl group, a methyl group, an isopropylgroup, a hydroxy group, a methoxy group or an acetoxy group, R⁸ and R⁹are the same or different and represent hydrogen atoms, hydroxy groups,methoxy groups, ethoxy groups, acetoxy groups, chloroacetoxy groups,butanoyloxy groups, methanesulfonyloxy groups; p-toluenesulfonyloxygroups, amino groups, acetamino groups, benzyloxycarabonylamino groups,methanesulfonyl groups, or together an ethylenedioxy group or acarbonyldioxy group, R¹⁰ represents a hydrogen atom, a hydroxy group, anacetoxy group, a methoxy group, or a chloracetoxy group, with theproviso that R⁷, R⁸, R⁹ and R¹⁰ do not represent hydrogen atoms at thesame time, R¹⁵ represents a hydrogen atom or a carboxyl-protectinggroup, and the bond shown with a wavy line represents a bond ofanti-form or syn-form.
 2. An intermediate compound as claimed in claim1, or salts, solvates or salts of solvates thereof, wherein the absoluteconfiguration of the carbon atom to which R² and R³ are connected is(S)-configuration, and the said bond shown with a wavy line represents abond of syn-form.
 3. An intermediate compound as claimed in claim 2, orsalts, solvates or salts of solvates thereof, wherein R² represents ahydrogen atom.
 4. An intermediate compound as claimed in claim 2, orsalts, solvates or salts of solvates thereof, wherein R⁷ and R¹⁰represent hydrogen atoms.
 5. An intermediate compound as claimed inclaim 4, or salts, solvates or salts of solvates thereof, wherein R⁸ andR⁹ are the same or different and represent hydroxy groups, acetoxygroups, chloracetoxy groups, or together an ethylenedioxy group or acarbonyldioxy group.
 6. An intermediate compound as claimed in claim 2,or salts, solvates or salts of solvates thereof, wherein R⁷ represents ahydrogen atom, R⁸, or R⁹ and R¹⁰ represent hydroxy groups, acetoxygroups or chloroacetoxy groups.